Peptide antiangiogenic drugs

ABSTRACT

Peptides having the formula: 
     
       
         A 0 -A 1 -A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10   
       
     
     wherein A 0  is selected from hydrogen or an acyl group; A 10  is a hydroxyl group or an amino acid amide; and A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , and A 9  are amino acyl residues as defined herein.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/316,888, filed May 21, 1999, pending, and claims the benefitof U.S. Provisional Patent Applications 60/126,546, filed Mar. 26, 1999and 60/086,536 filed May 21, 1998, both of which are hereby incorporatedby reference.

TECHNICAL FIELD

The invention relates to novel compounds having activity useful fortreating conditions which arise or are exacerbated by angiogenesis,pharmaceutical compositions comprising these compounds, a method oftreating using said compounds, and a method of inhibiting angiogensis.

BACKGROUND OF THE INVENTION

Angiogenesis is the fundamental process by which new blood vessels areformed and is essential to a variety of normal body activities (such asreproduction, development and wound repair). Although the process is notcompletely understood, it is believed to involve a complex interplay ofmolecules which both stimulate and inhibit the growth of endothelialcells, the primary cells of the capillary blood vessels. Under normalconditions, these molecules appear to maintain the microvasculature in aquiescent state (i.e. one of no capillary growth) for prolonged periodswhich may last for as long as weeks or in some cases, decades. Whennecessary however (such as during wound repair), these same cells canundergo rapid proliferation and turnover within a five day period.(Folkman, J. and Shing, Y., The Journal of Biological Chemistry,267(16): 10931-10934, and Folkman J. and Klagsbrun, M., Science, 235:442-447 (1987)).

Although angiogenesis is a highly regulated process under normalconditions, many diseases (characterized as “angiogenic diseases”) aredriven by persistent unregulated angiogenesis. Otherwise stated,unregulated angiogenesis may either cause a particular disease directlyor exascerbate an existing pathological condition. For example, ocularneovacularization has been implicated as the most common cause ofblindness. In certain existing conditions such as arthritis, newlyformed capillary blood vessels invade the joints and destroy cartilage.In diabetes, new capillaries formed in the retina invade the vitreous,bleed, and cause blindness. Growth and metastasis of solid tumors arealso angiogenesis-dependent (Folkman, J., Cancer Research, 46: 467-473(1986), Folkman, J., Journal of the National Cancer Institute, 82: 4-6(1989)). It has been shown for example that tumors which enlarge togreater than 2 mm, must obtain their own blood supply and do so byinducing the growth of new capillary blood vessels. Once these new bloodvessels become embedded in the tumor, they provide a means for tumorcells to enter the circulation and metastasize to distant sites, such asliver, lung or bone (Weidner, N., et al., The New England Journal ofMedicine, 324(1): 1-8 (1991)).

Although several angiogenesis inhibitors are currently under developmentfor use in treating angiogenic diseases (Gasparini, G. and Harris, A.L., J Clin Oncol 13(3): 765-782, (1995)), there are disadvantagesassociated with several of these compounds. For example, suramin is apotent angiogenesis inhibitor, but causes (at doses required to reachantitumor activity) severe systemic toxicity in humans. Other compounds,such as retinoids, interferons and antiestrogens are safe for human usebut have only a weak anti-angiogenic effect.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula:

A₀-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀  (I)

or a pharmaceutically acceptable salt, ester, solvate or prodrugthereof, wherein:

A₀ is an acyl group selected from:

(1) R—(CH₂)_(n)—C(O)—; wherein n is an integer from 0 to 8 and R isselected from hydroxyl; methyl; N-acetylamino; methoxyl; carboxyl;cyclohexyl optionally containing one or two double bonds and optionallysubstituted with one to three hydroxyl groups; and a 5- or 6-memberedaromatic or nonaromatic ring optionally containing one or twoheteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ringis optionally substituted with a moiety selected from alkyl, alkoxy, andhalogen;

 and

(2) R¹—CH₂CH₂—(OCH₂CH₂O)_(p)—CH₂—C(O)—; wherein R¹ is selected fromhydrogen, alkyl and N-acetylamino, and p is an integer from 1 to 8;

A₁ is an amino acyl residue selected from:

(1) alanyl,

(2) asparaginyl,

(3) citrullyl,

(4) glutaminyl,

(5) glutamyl,

(6) N-ethylglycyl,

(7) methionyl,

(8) N-methylalanyl,

(9) prolyl,

(10) pyro-glutamyl,

(11) sarcosyl,

(12) seryl,

(13) threonyl,

(14) —HN—(CH₂)_(q)—C(O)—, wherein q is 1 to 8, and

(15) —HN—CH₂CH₂—(OCH₂CH₂O)_(r)—CH₂—C(O)—, wherein r is 1 to 8;

A₂ is an amino acyl residue selected from:

(1) alanyl,

(2) asparaginyl,

(3) aspartyl,

(4) glutaminyl,

(5) glutamyl,

(6) leucyl,

(7) methionyl,

(8) phenylalanyl,

(9) prolyl,

(10) seryl,

(11) —HN—(CH₂)_(q)—C(O)—, wherein q is 1 to 8, and

(12) —HN—CH₂CH₂—(OCH₂CH₂O)_(r)—CH₂—C(O)—, wherein r is 1 to 8;

A₃ is an amino acyl residue selected from:

(1) alanyl,

(2) asparaginyl,

(3) citrullyl,

(4) cyclohexylalanyl,

(5) cyclohexylglycyl,

(6) glutaminyl,

(7) glutanyl,

(8) glycyl,

(9) isoleucyl,

(10) leucyl,

(11) methionyl,

(12) norvalyl,

(13) phenylalanyl,

(14) seryl,

(15) t-butylglycyl,

(16) threonyl,

(17) valyl,

(18) penicillaminyl, and

(19) cystyl;

A₄ is an amino acyl residue of L or D configuration selected from:

(1) allo-isoleucyl,

(2) glycyl,

(3) isoleucyl,

(4) prolyl,

(5) dehydroleucyl,

(6) D-alanyl,

(7) D-3-(naphth-1-yl)alanyl,

(8) D-3-(naphth-2-yl)alanyl,

(9) D-3-pyridyl)alanyl,

(10) D-2-aminobutyryl,

(11) D-allo-isoleucyl,

(12) D-allo-threonyl;

(13) D-allylglycyl,

(14) D-asparaginyl,

(15) D-aspartyl,

(16) D-benzothienyl,

(17) D-3-(4,4′-biphenyl)alanyl,

(18) D-chlorophenylalanyl,

(19) D-3-(3-trifluoromethylphenyl)alanyl,

(20) D-3-(3-cyanophenyl)alanyl,

(21) D-3-(3,4-difluorophenyl)alanyl,

(22) D-citrullyl,

(23) D-cyclohexylalanyl,

(24) D-cyclohexylglycyl,

(25) D-cystyl,

(26) D-cystyl(S-t-butyl),

(27) D-glutaminyl,

(28) D-glutamyl,

(29) D-histidyl,

(30) D-homoisoleucyl,

(31) D-homophenylalanyl,

(32) D-homoseryl,

(33) D-isoleucyl,

(34) D-leucyl,

(35) D-lysyl(N-epsilon-nicotinyl),

(36) D-lysyl,

(37) D-methionyl,

(38) D-neopentylglycyl,

(39) D-norleucyl,

(40) D-norvalyl,

(41) D-ornithyl,

(42) D-penicillaminyl,

(43) D-penicillaminyl(acetnidomethyl),

(44) D-penicillaminyl(S-benzyl),

(45) D-phenylalanyl,

(46) D-3-(4-aminophenyl)alanyl,

(47) D-3-(4-methylphenyl)alanyl,

(48) D-3-(4-nitrophenyl)alanyl,

(49) D-3-(3,4-dimethoxyphenyl)alanyl,

(50) D-3-(3,4,5-trifluorophenyl)alanyl,

(51) D-prolyl,

(52) D-seryl,

(53) D-seryl(O-benzyl),

(54) D-t-butylglycyl,

(55) D-thienylalanyl,

(56) D-threonyl,

(57) D-threonyl(O-benzyl),

(58) D-tryptyl,

(59) D-tyrosyl(O-benzyl),

(60) D-tyrosyl(O-ethyl),

(61) D-tyrosyl, and

(62) D-valyl;

A₅ is an amino acyl residue of L or D configuration selected from:

(1) alanyl,

(2) (3-pyridyl)alanyl,

(3) 3-(naphth-1-yl)alanyl,

(4) 3naphth-2-yl)alanyl,

(5) allo-threonyl,

(6) allylglycyl,

(7) glutaminyl,

(8) glycyl,

(9) histidyl,

(10) homoseryl,

(11) isoleucyl,

(12) lysyl(N-epsilon-acetyl),

(13) methionyl,

(14) norvalyl,

(15) octylglycyl,

(16) omithyl,

(17) 3-(4-hydromethylphenyl)alanyl,

(18) prolyl,

(19) seryl,

(20) threonyl,

(21) tryptyl,

(22) tyrosyl,

(23) D-allo-threonyl,

(24) D-homoseryl,

(25) D-seryl,

(26) D-threonyl,

(27) penicillaminyl, and

(28) cystyl;

A₆ is an amino acyl residue of L or D configuration selected from:

(1) alanyl,

(2) 3-(naphth-1-yl)alanyl,

(3) 3-(naphth-2-yl)alanyl,

(4) (3-pyridyl)alanyl,

(5) 2-aminobutyryl,

(6) allylglycyl,

(7) arginyl,

(8) asparaginyl,

(9) aspartyl,

(10) citrullyl,

(11) cyclohexylalanyl,

(12) glutaminyl,

(13) glutamyl,

(14) glycyl,

(15) histidyl,

(16) homoalanyl,

(17) homoleucyl,

(18) homoseryl,

(19) isoleucyl,

(20) leucyl,

(21) lysyl(N-epsilon-acetyl),

(22) lysyl(N-epsilon-isopropyl),

(23) methionyl(sulfone),

(24) methionyl(sulfoxide),

(25) methionyl,

(26) norleucyl,

(27) norvalyl,

(28) octylglycyl,

(29) phenylalanyl,

(30) 3-(4-carboxyamidephenyl)alanyl,

(31) propargylglycyl,

(32) seryl,

(33) threonyl,

(34) tryptyl,

(35) tyrosyl,

(36) valyl,

(37) D-3-(naphth-1-yl)alanyl,

(38) D-3-(naphth-2-yl)alanyl,

(39) D-glutaminyl,

(40) D-homoseryl,

(41) D-leucyl,

(42) D-norvalyl,

(43) D-seryl,

(44) penicillaminyl, and

(45) cystyl;

A₇ is an amino acyl residue of L or D configuration selected from:

(1) alanyl,

(2) allylglycyl,

(3) aspartyl,

(4) citrullyl,

(5) cyclohexylglycyl,

(6) glutamyl,

(7) glycyl,

(8) homoseryl,

(9) isoleucyl,

(10) allo-isoleucyl,

(11) leucyl,

(12) lysyl(N-epsilon-acetyl),

(13) methionyl,

(14) 3-(naphth-1-yl)alanyl,

(15) 3-(naphth-2-yl)alanyl,

(16) norvalyl,

(17) phenylalanyl,

(18) prolyl,

(19) seryl,

(20) t-butylglycyl,

(21) tryptyl,

(22) tyrosyl,

(23) valyl,

(24) D-allo-isoleucyl,

(25) D-isoleucyl,

(26) penicillaminyl, and

(27) cystyl;

A₈ is an amino acyl residue selected from:

(1) 2-amino4-[(2-amino)-pyrimidinyl]butanoyl,

(2) alanyl(3-guanidino),

(3) alanyl[3-pyrrolidinyl(2-N-amidino)],

(4) alanyl[4-piperidinyl(N-amidino)],

(5) arginyl,

(6) arginyl(N^(G)N^(G′) diethyl),

(7) citrullyl,

(8) 3-(cyclohexyl)alanyl(4N′-isopropyl),

(9) glycyl[4-piperidinyl(N-amidino)],

(10) histidyl,

(11) homoarginyl,

(12) lysyl,

(13) lysyl(N-epsilon-isopropyl),

(14) lysyl(N-epsilon-nicotinyl),

(15) norarginyl,

(16) ornithyl(N-delta-isopropyl),

(17) ornithyl(N-delta-nicotinyl),

(18) ornithyl[N-delta-(2-imidazolinyl)],

(19) [4-amino(N-isopropyl)methyl)phenyl]alanyl,

(20) 3-(4-guanidinophenyl)alanyl, and

(21) 3-(4-amino-N-isopropylphenyl)alanyl;

A₉ is an amino acyl residue of L or D configuration selected from:

(1) 2-amino-butyryl,

(2) 2-amino-isobutyryl,

(3) homoprolyl,

(4) hydroxyprolyl,

(5) isoleucyl,

(6) leucyl,

(7) phenylalanyl,

(8) prolyl,

(9) seryl,

(10) t-butylglycyl,

(11) 1,2,3,4-tetrahydroisoquinoline-3carbonyl,

(12) threonyl,

(13) valyl,

(14) D-alanyl, and

(15) D-prolyl; and

A₁₀ is a hydroxyl group or an amino acid amide is selected from:

(1) azaglycylamide,

(2) D-alanylamide,

(3) D-alanylethylamide,

(4) glycylamide,

(5) glycylethylamide,

(6) sarcosylamide,

(7) serylamide,

(8) D-serylamide,

(9) a group represented by the formula

 and

(9) a group represented by the formula —NH—R⁴;

 wherein:

s is an integer selected from 0 to 8,

R² is selected from hydrogen, alkyl, and a 5- to 6-membered cycloalkylring;

R³ is selected from hydrogen, hydroxy, alkyl, phenyl, alkoxy, and a 5-to 6-membered ring optionally containing from one to two heteroatomsselected from oxygen, nitrogen, and sulfur, provided that s is not zerowhen R³ is hydroxy or alkoxy; and

R⁴ is selected from hydrogen, hydroxy, and a 5- to 6-membered cycloalkylring.

In another aspect, the present invention provides a composition fortreating a patient in need of anti-angiogenesis therapy comprising apeptide defined above in pill combination with a pharmaceuticallyacceptable carrier.

Yet another aspect of the present invention provides a method fortreating a patient in need of anti-angiogenesis therapy comprisingadministering to the patient a therapeutically effective amount of apeptide as defined above.

Still yet another aspect of the present invention provides a compositionfor the treatment of a disease selected from cancer, arthritis,psoriasis, angiogenesis of the eye associated with infection or surgicalintervention, macular degeneration and diabetic retinopathy comprising apeptide as defined above in combination with a pharmaceuticallyacceptable carrier.

In yet another aspect, the present invention provides a method ofisolating a receptor from an endothelial cell comprising binding apeptide as defined above to the receptor to form a peptide receptorcomplex, isolating the peptide receptor complex, and purifying thereceptor.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

The term “alkyl” as used herein refers to a monovalent group derivedfrom a straight or branched chain saturated hydrocarbon by the removalof a hydrogen atom. Examples of alkyl include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, pentyl, hexyl, and the like. Preferred alkyl groups for theinvention are C₁-C₆ alkyl groups having from one to six carbon atoms.Alkyl groups of one to three carbon atoms (C₁-C₃ alkyl) are morepreferred for the invention.

The term “nicotinyl” as used herein refers to the acyl group derivedfrom nicotinic acid, i.e. pyridine-3-carboxylic acid. The term“2-Me-nicotinyl” or “2-methylnicotinyl” refers to a nicotinyl moietysubstituted with a methyl group at the carbon adjacent to the nitrogenatom.

The term “shikimyl” as used herein refers to the acyl residue derivedfrom shikimic acid or[3R-(3α,4α,5β)-3,4,5-trihydroxy]-1-cyclohexene-1-carboxylic acid. A“dihydroshikimyl” group denotes the fully saturated analog of shikimicacid.

The term “succinyl” as used herein refers to the acyl residue derivedfrom succinic acid or (1,4-dioxobutyl)-1-carboxylic acid.

The term “N-acetylamino” as used herein refers to an amino moiety (—NH₂)substituted on the nitrogen atom with an acetyl (CH₃C(O)—) group.

The term “carbonyl” as used herein refers to the group —C(O)—.

The term “carboxy” or “carboxyl” as used herein refers to the group—C(O)OH.

The term “alkoxy” as used herein refers to an alkyl group as definedabove attached to a parent molecular moiety via an ether linkage.Exemplary alkoxy groups include, but are not limited to, methoxy,ethoxy, isopropoxy, and the like.

The term “aromatic ring” as used herein refers to an unsaturated cyclichydrocarbon associated with a system of π-electron bonds. One to twocarbon atoms of the hydrocarbon ring can be substituted with aheteroatom selected from nitrogen, oxygen, or sulfur. Exemplary 5- or6membered aromatic rings include, but are not limited to, benzyl,pyridyl, furyl, tetrahydrofuryl, thienyl, and pyrrolyl. An aromaticring, including rings substituted with a heteroatom, can be optionallysubstituted on one or more carbon atoms with substituents selected fromalkyl, alkoxy, carboxy, and halogen, for example, tolyl, bromobenzyl,t-butylbenzyl, nicotinyl, 2-methylnicotinyl, 2-furoic acid, and thelike.

The term “nonaromatic ring” as used herein refers to a saturated orunsaturated cyclic hydrocarbon ring, which can be optionally substitutedwith one or two heteroatoms selected from nitrogen, oxygen, or sulfur.Exemplary nonaromatic rings are cyclohexyl, tetrahydropyranyl,pyrrolidinyl, and piperidinyl.

The term “N-protecting group” as used herein refers to an easilyremovable group which is known in the art to protect an amino groupagainst undesirable reaction during synthetic procedures and to beselectively removable. The use of N-protecting groups is well known inthe art for protecting groups against undesirable reactions during asynthetic procedure and many such protecting groups are known, cf, forexample, T. H. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd edition, John Wiley & Sons, New York (1991). Examples ofN-protecting groups include, but are not limited to, acyl groupsincluding acetyl, trifluoroacetyl, acylisothiocyanate, aminocaproyl,benzoyl and the like, and acyloxy groups, including t-butyloxycarbonyl(Boc) and carbobenzyloxy (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), andthe like.

As used herein the terms “Leu,” “Sar,” “Gln,” “Gly,” “Val,” “Ile,”“Thr,” “Nva,” “Arg,” “Asn,” “pyroGlu,” “Ser,” “Ala,” “Homoala,” “Cha,”“Pro”, “Phe,” “Trp,” “1-Nal,” “2-Nal,” “Azagly” and “Nle” refer toleucine, sarcosine (N-methylglycine), glutamine, glycine, valine,isoleucine, threonine, norvaline, arginine, aspargine, pyroglutamicacid, serine, alanine, homoalanine, cyclohexylalanine, proline,phenylalanine, tryptophan, 1-naphthylalanine, 2-naphthylalanine,azaglycine, and norleucine, respectively, in their L-, D- or DL forms.Unless indicated otherwise by a “D” prefix, e.g. D-Ala or D-Ile (alsoD-Ile), the stereochemistry of the α-carbon of the amino acids andaminoacyl residues in peptides described in this specification and theappended claims is the natural or “L” configuration. TheCahn-Ingold-Prelog “R” and “S” designations are used to specify thestereochemistry of chiral centers in certain of the acyl substituents atthe N-terminus of the peptides of this invention. The designation “R,S”is meant to indicate a racemic mixture of the two enantiomeric forms.This nomenclature follows that described in R. S. Cahn, et al., Angew.Chem. Int. Ed. Engl., 5, 385-415 (1966).

For the most part, the names on naturally occurring and non-naturallyoccurring aminoacyl residues used herein follow the naming conventionssuggested by the IUPAC Commission on the Nomenclature of OrganicChemistry and the IUPAC-IUB Commission on Biochemical Nomenclature asset out in “Nomenclature of α-Amino Acids (Recommendations, 1974)”Biochemistry, 14(2), (1975). To the extent that the names andabbreviations of amino acids and aminoacyl residues employed in thisspecification and appended claims differ from those suggestions, theywill be made clear to the reader. Some abbreviations useful indescribing the invention are defined below in the following Table 1.

TABLE 1 Abbreviation Definition Abu 2-aminobutyric acid 6-NAc-caproyl,6-N-Ac-(CH₂)₅C(O)—, or 6-Ac-Aca 6-N-acetyl-aminocaproic acid Aib2-aminoisobutyric acid Ala(3-guanidino) alanine(3-guanidino)Ala(3-pyrrolidinylamidino) alanine[3-pyrrolidinyl(2-N-amidino)]Ala[4-Pip(N-amidino)] alanine[4-piperidinyl(N-amidino)] Allylgly2-(allyl)glycine AM aminomethyl Aminopyrimidinobutanoyl 2-amino-4-[(2-amino)pyrimidinyl]butanoic acid Azagly azaglycine 3-Ac-Bala3-N-acetyl-beta-alanine Bala beta-alanine Cha 3-(cyclohexyl)alanineCha(4-NIsp) 3-(cyclohexyl)alanine(4-N′-isopropyl) Cit citrulline 2ClTrt2-chloro-trityl Cys(tBu) cysteine(S-t-butyl) D-2-ThienylalaD-3-(2-thienyl)alanine D-3,3-Diphenylala D-3,3-(diphenyl)alanineD-3,4-diClPhe D-3-(3,4-dichlorophenyl)alanine D-3,4-diFPheD-3-(3,4-difluorophenyl)alanine D-3-BenzothienylalaD-3-(3-benzothienyl)alanine D-3-CF₃PheD-3-(3-trifluoromethylphenyl)alanine D-3-ClPheD-3-(3-chlorophenyl)alanine D-3-CNPhe D-3-(3-cyanophenyl)alanine D-3-PalD-(3-pyridyl)alanine D-4,4′-Biphenylala D-3-(4,4′-biphenyl)alanineD-4-ClPhe D-3-(4-chloro-phenyl)alanine D-Cha D-3-(cyclohexyl)alanineD-Chg D-cyclohexylglycine Dehydroleu dehydroleucine D-HpheD-homophenylalanine D-Ile D-isoleucine D-alloIle D-allo-isoleucineD-Lys(Nic) D-lysine(N-epsilon-nicotinyl) D-Leu D-leucine D-pentaFPheD-3-(pentafluorophenyl)alanine D-Val D-valine 4-Ac-Gaba4-N-acetyl-gamma-aminobutyric acid or 4-N-acetyl-4-aminobutyric acidGaba gamma-aminobutyric acid or 4-aminobutyric acidGly[4-Pip(N-amidino)] glycine[4-piperidinyl(N-amidino)] Harghomoarginine Hle homoleucine Hser homoserine Hyp 4-hydroxyproline Ispisopropyl Lys(Ac) lysine(N-epsilon-acetyl) Lys(Isp)lysine(N-epsilon-isopropyl) Lys(Nic) lysine(N-epsilon-nicotinyl) Met(O)methionine sulfoxide Met(O₂) methionine sulfone MeOAc or (MeO)acetylmethoxyacetyl 1Nal 3-(naphth-1-yl)alanine 2Nal 3-(naphth-2-yl)alanineN-Ac-Sar N-acetylsarcosine Neopentylgly neopentylglycine NEtGlyN-ethylglycine Norarg norarginine Octylgly 2-(octyl)glycine Orn(Ac)ornithine(N-delta-acetyl) Orn(2-imidazo)ornithine[N-delta-(2-imidazolinyl)] Orn(Isp)ornithine(N-delta-isopropyl) Orn(Nic) ornithine(N-delta-nicotinyl)O-TBDMS O-t-butyldimethylsilyl Pen penicillamine or β,β-dimethylcysteinePen(Acm) penicillamine(acetamidomethyl) D-Phe(3,4,5-triF)D-3-(3,4,5-trifluorophenyl)alanine D-Phe(3,4-diMeO)D-3-(3,4-dimethoxyphenyl)alanine Phe(4-CH₂OH)3-(4-hydroxymethylphenyl)alanine Phe(4-CONH₂)3-(4-carboxyamidephenyl)alanine Phe(4-guanidino)3-(4-guanidinophenyl)alanine D-Phe(4-Me) D-3-(4-methylphenyl)alanineD-Phe(4-NH₂) D-3-(4-aminophenyl)alanine Phe(4-NIsp)3-(4-amino-N-isopropylphenyl)alanine Phe(4-CH₂NHIsp) [(4-amino(N-isopropyl)methyl)phenyl]alanine D-Phe(4-NO₂) D-3-(4-nitrophenyl)alaninePropargylgly propargylglycine Pip pipecolic acid or homoproline pyBropbromo-tris- pyrrolidinophosphoniumhexafluorophosphate Ser(Bzl)serine(O-benzyl) tButylgly t-butylglyine Thr(Bzl) threonine(O-benzyl)Tic 1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid Trt tritylTyr(Bzl) tyrosine(O-benzyl) Tyr(Et) tyrosine(O-ethyl) THFtetrahydrofuryl or tetrahydrofuran 2-THFcarbonyl(tetrahydro-2-furyl)carbonyl

When not found in the table above, nomenclature and abbreviations may befurther clarified by reference to the Calbiochem-Novabiochem Corp. 1999Catalog and Peptide Synthesis Handbook or the Chem-Impex International,Inc. Tools for Peptide & Solid Phase Synthesis 1998-1999 Catalogue.

The term “pharmaceutically acceptable salt” as used herein refers tosalts which are, within the scope of sound medical judgement, suitablefor use in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1-19. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Representative acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like, as well asnontoxic ammonium, quaternary ammonium, and amine cations, including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable solvate” represents an aggregatethat comprises one or more molecules of the solute, such as a formula(I) compound, with one or more molecules of solvent.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgement, suitable for use in contactwith with the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “receptor” as used herein refers to a chemical group ormolecule on the cell surface or in the cell interior that has anaffinity for a specific chemical group, molecule, or virus. Isolation ofreceptors relevant to the antiangiogenic activity of the peptide of theinvention can provide useful diagnostic tools.

In one embodiment, the present invention relates to compounds of thestructure

A₀-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀  (I)

wherein A₀, A₁, A₂, A₃, A₇, A₈, A₉, and A₁₀ are as defined above. TheN-terminus of a nonapeptide represented by A₁-A₉ can be modified by anamino acyl group represented by A₀. A₁₀ represents a group suitable formodifying the C-terminus of the compound.

In the present embodiment, As is an amino acyl residue having a Dconfiguration selected from D-allo-isoleucyl, D-allylglycyl,D-3-(3-cyanophenyl)alanyl, D-cystyl, D-isoleucyl, D-leucyl,D-penicillaminyl, D-phenylalanyl, D-3-(3,4,5-trifluorophenyl)alanyl, andD-3-(4-aminophenyl)alanyl; A₅ is an amino acyl residue selected fromoctylglycyl, glycyl, penicillaminyl, seryl, threonyl, and tyrosyl; andA₆ is an amino acyl residue selected from glutaminyl, leucyl, norvalyl,and seryl.

In another embodiment of the invention, the compounds have the structure(I) as defined above wherein A₁ is sarcosyl, A₂ is glycyl, A₃ is valyl,A₇ is isoleucyl, A₈ is arginyl, and A₉ is prolyl. Compounds of thepresent embodiment can be represented by the structure

A₀-Sar-Gly-Val-A₄-A₅-A₆-Ile-Arg-Pro-A₁₀  (II)

wherein A₀ is hydrogen or an acyl group modifying the N-terminus.Suitable groups for A₀ can represented by the formula R—(CH₂)_(n)—C(O)—;wherein n is an integer from 0 to 8 and R is selected from hydroxyl;methyl; N-acetylamino; methoxyl; carboxyl; cyclohexyl optionallycontaining a one or two double bonds and optionally substituted with oneto three hydroxyl groups; and a 5- or 6-membered ring aromatic ornonaromatic ring optionally containing one or two heteroatoms selectedfrom nitrogen, oxygen, and sulfur, wherein the ring is optionallysubstituted with a moiety selected from alkyl, alkoxy, and halogen; orR¹—CH₂CH₂—(OCH₂CH₂O)_(p)—CH₂—C(O)—; wherein R¹ is selected fromhydrogen, alkyl, and N-acetylamino, and p is an integer from 1 to 8.

A₄ is an amino acyl residue of L or D configuration selected fromallo-isoleucyl, dehydroleucyl, glycyl, isoleucyl, prolyl, D-alanyl,D-3-(naphth-1-yl)alanyl, D-3-(naphth-2-yl)alanyl, D-(3-pyridyl)-alanyl,D-2-aminobutyryl, D-allo-isoleucyl, D-allo-threonyl, D-allylglycyl,D-asparaginyl, D-aspartyl, D-benzothienyl, D-3-(4,4′-biphenyl)alanyl,D-chlorophenylalanyl, D-3-(3-trifluoromethylphenyl)alanyl,D-3-(3cyanophenyl)alanyl, D-3-(3,4difluorophenyl)alanyl, D-citrullyl,D-cyclohexylalanyl, D-cyclohexylglycyl, D-cystyl, D-cystyl(S-t-butyl),D-glutaminyl, D-glutamyl, D-histidyl, D-homoisoleucyl,D-homophenylalanyl, D-homoseryl, D-isoleucyl, D-leucyl,D-lysyl(N-epsilon-nicotinyl), D-lysyl, D-methionyl, D-neopentylglycyl,D-norleucyl, D-norvalyl, D-ornithyl, D-penicillaminyl,D-penicillaminyl(acetamidomethyl), D-penicillaminyl(S-benzyl),D-phenylalanyl, D-3-(4-aminophenyl)alanyl, D-3-(4-methylphenyl)alanyl,D-3-(4-nitro-phenyl)alanyl, D-3-(3,4-dimethoxyphenyl)alanyl,D-3-(3,4,5-trifluorophenyl)alanyl, D-prolyl, D-seryl, D-seryl(O-benzyl),D-t-butylglycyl, D-thienylalanyl, D-threonyl, D-threonyl(O-benzyl),D-tryptyl, D-tyrosyl(O-benzyl), D-tyrosyl(O-ethyl), D-tyrosyl, andD-valyl.

A₅ is an amino acyl residue, of L or D configuration selected fromalanyl, (3-pyridyl)-alanyl, 3-(naphth-1-yl)alanyl, 3naphth-2-yl)alanyl,allo-threonyl, allylglycyl, glutaminyl, glycyl, histidyl, homoseryl,isoleucyl, lysyl(N-epsilon-acetyl), methionyl, norvalyl, octylglycyl,ornithyl, 3-(4-hydroxymethylphenyl)alanyl, prolyl, seryl, threonyl,tryptyl, tyrosyl, D-allo-threonyl, D-homoseryl, D-seryl, D-threonyl,penicillaminyl, and cystyl.

A₆ is an amino acyl residue of L or D configuration selected fromalanyl, 3-(naphth-1-yl)alanyl, 3-(naphth-2-yl)alanyl, (3-pyridyl)alanyl,2-aminobutyryl, allylglycyl, arginyl, asparaginyl, aspartyl, citrullyl,cyclohexylalanyl, glutaminyl, glutamyl, glycyl, histidyl, homoalanyl,homoleucyl, homoseryl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl),lysyl(N-epsilon-isopropyl), methionyl(sulfone), methionyl(sulfoxide),methionyl, norleucyl, norvalyl, octylglycyl, phenylalanyl,3-(carboxyamidephenyl)alanyl, propargylglycyl, seryl, threonyl, tryptyl,tyrosyl, valyl, D-3-(naphth-1-yl)alanyl, D-3-(naphth-2-yl)alanyl,D-glutaminyl, D-homoseryl, D-leucyl, D-norvalyl, D-seryl,penicillaminyl, and cystyl.

A₁₀ is a hydroxyl group or an amino acid amide selected fromazaglycylamide, D-alanylamide, D-alanylethylamide, glycylamide,glycylethylamide, sarcosylamide, serylamide, D-serylamide, or A₁₀ is agroup represented by the formula

or a group represented by the formula —NH—R⁴, wherein s is an integerselected from 0 to 8; R² is selected from hydrogen, alkyl, and a 5- to6-membered cycloalkyl ring; R³ is selected from hydrogen, hydroxy,alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containingfrom one to two heteroatoms selected from oxygen, nitrogen, and sulfur,provided that s is not zero when R³ is hydroxy or alkoxy; and R⁴ isselected from hydrogen, hydroxy, and a 5- to 6-membered cycloalkyl ring.

Preferred compounds of the invention have the structure (II) as definedabove, wherein A₄ is an amino acyl residue having a D configurationselected from D-alanyl, D-3-(naphth-1-yl)alanyl, D-3 naphth-2-yl)alanyl,D-(3-pyridyl)-alanyl, D-2-aminobutyryl, D-allo-isoleucyl,D-allo-threonyl, D-allylglycyl, D-asparaginyl, D-aspartyl,D-chloro-phenylalanyl, D-3-(3-trifluoromethylphenyl)alanyl,D-3-(3-cyanophenyl)alanyl, D-3-(3,4-difluorophenyl)alanyl,D-cyclohexylalanyl, D-cyclohexylglycyl, D-cystyl, D-glutaminyl,D-glutamyl, D-histidyl, D-homoisoleucyl, D-homophenylalanyl,D-homoseryl, D-isoleucyl, D-leucyl, D-lysyl(N-epsilon-nicotinyl),D-methionyl, D-neopentylglycyl, D-norleucyl, D-norvalyl,D-penicillaminyl, D-penicillaminyl(acetamidomethyl),D-penicillaminyl(S-benzyl), D-phenylalanyl, 3(4-aminophenyl)alanyl,D-3-(4-methylphenyl)alanyl, D-3(4-nitrophenyl)alanyl,D-3(3,4-dimethoxyphenyl)alanyl, D-3-(3,4,5-trifluorophenyl)alanyl,D-prolyl, D-seryl, D-seryl(O-benzyl), D-t-butylglycyl, D-thienylalanyl,D-threonyl, D-threonyl(O-benzyl), D-tyrosyl(O-ethyl), D-tyrosyl,D-valyl, and D-cystyl.

Other preferred compounds of the present invention have the structure offormula (II), wherein A₅ is selected from glycyl, octylglycyl,penicillaminyl, seryl, threonyl, and tyrosyl.

Additional preferred compounds of the present invention have thestructure represented by formula (II), wherein A₆ is selected fromglutaminyl, leucyl, norvalyl, and seryl.

The more preferred amino acid residues for substituting the positionrepresented by A₄ are D configuration amino acids selected fromD-allo-isoleucyl, D-allylglycyl, D-3-(3-cyanophenyl)alanyl, D-cystyl,D-isoleucyl, D-leucyl, D-penicillaminyl, D-phenylalanyl,D-3-(3,4,5-trifluorophenyl)alanyl, and D-3-(4aminophenyl)alanyl.

Preferred A₀ groups for modifying the N-terminus of the compounds in thescope of the invention are selected from acetyl, butyryl, caproyl,(4N-acetylamino)butyryl, N-acetyl-beta-alanyl, (6-N-acetylamino)caproyl,chloronicotinyl, cyclohexylacetyl, furoyl, gamma-aminobutyryl,2-methoxyacetyl, methylnicotinyl, nicotinyl, (8-N-acetylamino)-3,6-dioxo-octanoyl, phenylacetyl, propionyl, shikimyl, succinyl, andtetrahydrofuroyl.

The preferred A₁₀ groups for modifying the C-terminus of the inventionare selected from D-alanylamide, azaglycylamide, serylamide, ethylamide;hydroxylamide, isopropylamide, propylamide, 2-(cyclohexyl)ethylamide,2-(1-pyrrolidine)ethylamide, 1-(cyclohexyl)ethylamide,2-(methoxy)ethylamide, 2-hydroxy)ethylamide, 2-(2-pyridine)ethylamide,(2-pyridine)methylamide, 2-(3-pyridine)ethylamide,2-(2-(1-methyl)pyrrolidine)ethylamide, 2-(N-morpholine)ethylamide, andcyclopropylmethylamide.

Compounds contemplated as failing within the scope of the presentinvention include, but are not limited to:

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

pyroGlu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂-(1-pyrrolidine),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethylpiperidine,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHmethylcyclopropyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(ethyl-1-(R)-cyclohexyl),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂cyclohexyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-Gly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Met-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-4,4′-Biphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-4-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-Dehydroleu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-CF₃Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-DNva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Abu-Ile-Arg-ProNHCH₂CH₃

N-Ac-Sar-Gly-Val-D-Ile-Thr-Allylgly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Octylgly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Met-Ile-Arg-ProNHCH₂CH₃,

N-Cyclohexylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Nicotinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Propionyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(MeO)acetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Butyryl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N—[CH₃CONH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

N[6-N-acetyl-(CH₂)5C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-[4-N-Acetylaminobutyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

H-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Gly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Ala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Il-Thr-Leu-Il-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-AbuNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Phe-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Tic-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Hyp-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Aib-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-Ala-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pip-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Tyr(Et)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys(tBu)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Tyr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ser(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-tButylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(4-Me )-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4-diMeO)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-(4-NO₂)Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-N-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Met-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ile-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ile-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Cit-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O₂)-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-Azagly-NH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Sar-NHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂,

N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Leu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Phe-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Glu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Asn-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Cit-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Glu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Gaba-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Bala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Gln-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Gly-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Glu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Asp-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Asn-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O)-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cit-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Hcit-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Hle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Phe(4-CONH₂)-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Isp)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Nic)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(Nic)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ile-Thr-Nva-Ile-Orn(Isp)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-NIsp)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cha(4-NIsp)ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Harg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Norarg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cit-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Phe(4-CH₂OH)-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-guanidino)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Aminopyrimidinylbutanoyl-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-CH₂NHlsp)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Gly[4-Pip(N-amidino)]-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala[4Pip(N-amidino)]-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala-(3-guanidino)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-pyrrolidinylamidino)-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(2-imidazo)-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃₎ ₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂(CH₃₎ ₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-SarNH₂,

N-Ac-Sar-Gly-Val-Ile-Thr-Gln-Ile-Arg-Pro-SarNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-SarNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH₂(CH₃),

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Orn(Ac)-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃),

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH2,

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH_(32,)

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-AzaglyNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHethyl-(1-pyrrolidine),

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNH(ethyl-1-cyclohexyl),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHethyl-(1-pyrrolidine),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl),

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl),

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH CH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-ProNHCH₂(CH₃),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHOH,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Nva-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Ile-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Leu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Ser-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Ala-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Ala-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Val-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Val-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-D-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-D-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-Leu-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃),

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-His-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloThr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloThr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloThr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloThr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(S)-cyclohexyl),

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Cys-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Re-Arg-Pro-D-AlaNH₂,

N-Succinyl-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Pen-D-Il-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃),

N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-Pro-D-AlaNH₂.

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gly-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Say-Ala-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH₂(CH₃₎ ₂,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH2,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-Pro-OH,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH,

N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-Pro-OH

N-Ac-Sar-Gly-Asp-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Ala-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Cha-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Met-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Hser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-His-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-Butyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Butyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Amyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-hexyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3,3-dimethyl)butyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH2-ethoxy)ethyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-isopropoxy)ethyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3-methoxy)propyl,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(cyclopentyl)methyl, and

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-cyclohexyl.

Preferred compounds for the practice of the invention are:

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂(1-pyrrolidine),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(ethyl-1-(R)-cyclohexyl),

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃,

N[2-THFcarbonyl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N[6-N-acetyl(CH₂)₅C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-[4-N-Acetylaminobutyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃.

N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂(CH₃)₂,

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.

It is well known in the art that modifications and changes can be madein the structure of a polypeptide without substantially altering thebiological function of that peptide. For example, certain amino acidscan be substituted for other amino acids in a given polypeptide withoutany appreciable loss of function. In making such changes, substitutionsof like amino acid residues can be made on the basis of relativesimilarity of side-chain substituents, for example, their size, charge,hydrophobicity, hydrophilicity, and the like.

In describing the invention, certain abbreviations are used for the sakeof convenience throughout the specification, including the examples, torefer to reagents and compounds useful for preparing the compounds ofthe invention. When so used, the following abbreviations are meant torefer to the following: DMF for dimethylformamide; DMA fordimethylacetamide; DIEA for diisopropylethylamine; HATU forO-(7-aza-benzotriazol-1-yl)-N,N,N′,N ′-tetramethyluroniumhaxafluorophosphate; NMP for N-methylpyrrolidone; and TFA fortrifluoroacetic acid.

Determination of Biological Activity Pellet Preparation

Ten microliters of a mixture containing a final concentration of 1, 5,or 10 mM of the peptides of invention, 100 ng of bFGF (CollaborativeBiomedical Products, Bedford, Mass.), and 6% Hydron (Sigma, St. Louis,Mo.) were pipetted into the tip of a sterile TeFlon rod. After dryingfor 1-2 hours, the pellets were stored at 4° C.

Pellet Implantation

A small (about 2 mm) radial incision at 1 mm from the center of thecornea was performed in anesthetized Sprague Dawley rats. With a curvediris spatula, an intrastromal pocket was made to a distance of 1 mm fromthe limbus-the circular blood vessels that surround the cornea. A singlepellet was implanted. Antibiotic ointment (neosporin) was applied postsurgery to the operated eye to prevent infection and to decreaseinflammation.

Data Analysis

At day seven post-implantation, neovascularization was measured througha slitlamp biomicroscopy (Nikon NS-1), connected to an image analysissystem (Leica Qwin). The response was calculated by colorimetricallydetecting the area of new blood vessels, and calculating the new vesselsurface area in μm². The compounds of the invention inhibit rat corneaneovascularization as shown in Table 2.

TABLE 2 Effect of the Compounds of the Invention on Rat CorneaNeovascularization Peptide Number of Corneas/Dose % Inhibition Example 16/10 μM 92.6 Example 1 5/5 μM 74.8 Example 1 4/6 μM 71.5 untreated 5/— —

The compounds of the invention, including but not limited to thosespecified in the examples, possess anti-angiogenic activity. Asangiogenesis inhibitors, such compounds are useful in the treatment ofboth primary and metastatic solid tumors, including carcinomas ofbreast, colon, rectum, lung, oropharynx, hypopharynx, esophagus,stomach, pancreas, liver, gallbladder and bile ducts, small intestine,urinary tract (including kidney, bladder and urothelium), female genitaltract, (including cervix, uterus, and ovaries as well as choriocarcinomaand gestational trophoblastic disease), male genital tract (includingprostate, seminal vesicles, testes and and germ cell tumors), endocrineglands (including the thyroid, adrenal, and pituitary glands), and skin,as well as hemangiomas, melanomas, sarcomas (including those arisingfrom bone and soft tissues as well as Kaposi's sarcoma) and tumors ofthe brain, nerves, eyes, and meninges (including astrocytomas, gliomas,glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas,and meningiomas). Such compounds may also be useful in treating solidtumors arising from hematopoietic malignancies such as leukemias (i.e.chloromas, plasmacytomas and the plaques and tumors of mycosis fungoidesand cutaneous T-cell lymphoma/leukemia) as well as in the treatment oflymphomas (both Hodgkin's and non-Hodgkin s lymphomas). In addition,these compounds may be useful in the prevention of metastases from thetumors described above either when used alone or in combination withradiotherapy and/or other chemotherapeutic agents.

Further uses include the treatment and prophylaxis of autoimmunediseases such as rheumatoid, immune and degenerative arthritis; variousocular diseases such as diabetic retinopathy, retinopathy ofprematurity, corneal graft rejection, retrolental fibroplasia,neovascular glaucoma, rubeosis, retinal neovascularization due tomacular degeneration, hypoxia, angiogenesis in the eye associated withinfection or surgical intervention, and other abnormalneovascularization conditions of the eye; skin diseases such aspsoriasis; blood vessel diseases such as hemagiomnas, and capillaryproliferation within atherosclerotic plaques; Osler-Webber Syndrome;myocardial angiogenesis; plaque neovascularization; telangiectasia;hemophiliac joints; angiofibroma; and wound granulation. Other usesinclude the treatment of diseases characterized by excessive or abnormalstimulation of endothelial cells, including but not limited tointestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, andhypertrophic scars, i.e. keloids. Another use is as a birth controlagent, by inhibiting ovulation and establishment of the placenta. Thecompounds of the invention are also useful in the treatment of diseasesthat have angiogenesis as a pathologic consequence such as cat scratchdisease (Rochele minalia quintosa) and ulcers (Helicobacter pylori). Thecompounds of the invention are also useful to reduce bleeding byadministration prior to sugery, especially for the treatment ofresectable tumors.

The compounds of the invention may be used in combination with othercompositions and procedures for the treatment of diseases. For example,a tumor may be treated conventionally with surgery, radiation orchemotherapy combined with a peptide of the present invention and then apeptide of the present invention may be subsequently administered to thepatient to extend the dormancy of micrometastases and to stabilize andinhibit the growth of any residual primary tumor. Additionally, thecompounds of the invention may be combined with pharmaceuticallyacceptable excipients, and optionally sustained-release matrices, suchas biodegradable polymers, to form therapeutic compositions.

A sustained-release matrix, as used herein, is a matrix made ofmaterials, usually polymers, which are degradable by enzymatic oracid-base hydrolysis or by dissolution. Once inserted into the body, thematrix is acted upon by enzymes and body fluids. A sustained-releasematrix desirably is chosen from biocompatible materials such asliposomes, polylactides (polylactic acid), polyglycolide (polymer ofglycolic acid), polylactide co-glycolide (copolymers of lactic acid andglycolic acid) polyanhydrides, poly(ortho)esters, polypeptides,hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fattyacids, phospholipids, polysaccharides, nucleic acids, polyamino acids,amino acids such as phenylalanine, tyrosine, isoleucine,polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.A preferred biodegradable matrix is a matrix of one of eitherpolylactide, polyglycolide, or polylactide co-glycolide (co-polymers oflactic acid and glycolic acid).

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention may be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt form. By a “therapeutically effective amount” of the compound ofthe invention is meant a sufficient amount of the compound to treat anangiogenic disease, (for example, to limit tumor growth or to slow orblock tumor metastasis) at a reasonable benefit/risk ratio applicable toany medical treatment. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific therapeutically effective dose level forany particular patient will depend upon a variety of factors includingthe disorder being treated and the severity of the disorder, activity ofthe specific compound employed; the specific composition employed, theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidential with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than those required to achieve the desired therapeutic effect andto gradually increase the dosage until the desired effect is achieved.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate,hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate,p-toluenesulfonate and undecanoate. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as acetic acid, maleic acid, succinic acid and citric acid. Othersalts include salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium or with organic basis. Preferredsalts of the compounds of the invention include phosphate, tris andacetate.

Alternatively, a compound of the present invention may be administeredas pharmaceutical compositions containing the compound of interest incombination with one or more pharmaceutically acceptable excipients. Apharmaceutically acceptable carrier or excipient refers to a non-toxicsolid, semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. The compositions may be administeredparenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, drops or transdermal patch),rectally, or bucally. The term “parenteral” as used herein refers tomodes of administration which include intravenous, intramuscular,intraperitoneal, intaasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically-acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity may be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorption,such as aluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide,poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions which are compatible with body tissues.

The injectable formulations may be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Topical administration includes administration to the skin or mucosa,including surfaces of the lung and eye. Compositions for topicaladministration, including those for inhalation, may be prepared as a drypowder which may be pressurized or non-pressurized. In non-pressurizedpowder compositions, the active ingredient in finely divided form may beused in admixture with a larger-sized pharmaceutically-acceptable inertcarrier comprising particles having a size, for example, of up to 100micrometers in diameter. Suitable inert carriers include sugars such aslactose. Desirably, at least 95% by weight of the particles of theactive ingredient have an effective particle size in the range of 0.01to 10 micrometers.

Alternatively, the composition may be pressurized and contain acompressed gas, such as nitrogen or a liquified gas propellant. Theliquified propellant medium and indeed the total composition ispreferably such that the active ingredient does not dissolve therein toany substantial extent. The pressurized composition may also contain asurface active agent, such as a liquid or solid non-ionic surface activeagent or may be a solid anionic surface active agent. It is preferred touse the solid anionic surface active agent in the form of a sodium salt.

A further form of topical administration is to the eye. A compound ofthe invention is delivered in a pharmaceutically acceptable ophthalmicvehicle, such that the compound is maintained in contact with the ocularsurface for a sufficient time period to allow the compound to penetratethe corneal and internal regions of the eye, as for example the anteriorchamber, posterior chamber, vitreous body, aqueous humor, vitreoushumor, cornea, iris/ciliary, lens, choroid/retina and sclera. Thepharmaceutically-acceptable ophthalmic vehicle may, for example, be anointment, vegetable oil or an encapsulating material. Alternatively, thecompounds of the invention may be injected directly into the vitreousand aqueous humour.

Compositions for rectal or vaginal administration are preferablysuppositories which may be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention may also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they may also be used in combination withone or more agents which are conventionally administered to patients fortreating angiogenic diseases. For example, the compounds of theinvention are effective over the short term to make tumors moresensitive to traditional cytotoxic therapies such as chemicals andradiation. The compounds of the invention also enhance the effectivenessof existing cytotoxic adjuvant anticancer therapies. The compounds ofthe invention may also be combined with other antiangiogenic agents toenhance their effectiveness, or combined with other antiangiogenicagents and administered together with other cytoioxic agents. Inparticular, when used in the treatment of solid tumors, compounds of theinvention may be administered with IL-12, retinoids, interferons,angiostatin, endostatin, thalidomide, thrombospondin-1,thrombospondin-2, captopryl, angioinhibins, TNP470, pentosanpolysulfate, platelet factor 4, LM609, SU-5416, CM-101, Tecogalan,plasminogen-K-5, vasostatin, vitaxin, vasculostatin, squalamine,marimastat or other MMP inhibitors, anti-neoplastic agents such as alphainteferon, COMP (cyclophosphamide, vincristine, methotrexate andprednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin,cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin,cyclophosphamide, cisplatin, taxol, etoposide/mechlorethamine,vincristine, prednisone and procarbazine), vincristine, vinblastine, andthe like as well as with radiation.

Total daily dose of the compositions of the invention to be administeredto a human or other mammal host in single or divided doses may be inamounts, for example, from 0.0001 to 300 mg/kg body weight daily andmore usually 1 to 300 mg/kg body weight.

It will be understood that agents which can be combined with thecompound of the present invention for the inhibition, treatment orprophylaxis of angiogenic diseases are not limited to those listedabove, but include in principle any agents useful for the treatment orprophylaxis of angiogenic diseases.

The peptides of the invention may be used for the development ofaffinity columns for isolation of receptors relevant to theantiangiogenic activity of the peptide of the invention, e.g. TSP-1receptor, in, for example, cultured endothelial cells. As is known inthe art, isolation and purification of the receptor may be followed byamino acid sequencing to identify and isolate polynucleotides whichencode the receptor. Recombinant expression of this receptor would allowgreater amounts of receptor to be produced, e.g. to produce a sufficientquantity for use in high throughput screening assays to identify otherangiogenesis inhibitors.

The peptides of the present invention may be chemically coupled toisotopes, enzymes, carrier proteins, cytotoxic agents, fluorescentmolecules, chemiluminescent, bioluminescent and other compounds for avariety of applications. For example, a peptide may be labeled tofacilitate testing of its ability to bind antisera or to detect celltypes which possess a relevant receptor. The coupling technique isgenerally chosen on the basis of the functional groups available on theamino acids of the peptide including, but not limited to amino,sullhydral, carboxyl, amide, phenol, and imidazole. Various reagentsused to effect such couplings include among others, glutaraldehyde,diazodized benzidine, carbodiimide, and p-benzoquinone.

The efficiency of the coupling reaction is determined using differenttechniques appropriate for the specific reaction. For example,radiolabeling of the peptide with I¹²⁵ may be accomplished usingchloramine T and NaI¹²⁵ of high specific activity. The reaction isterminated with sodium metabisulfite and the mixture is desalted ondisposable columns. The labeled peptide is eluted from the column andfractions are collected. Aliquots are removed from each fraction andradioactivity measured in a gamma counter. In this manner, a labeledpeptide may be obtained which is free from unreacted NaI¹²⁵.

The peptides of the present invention can also be used as antigens togenerate polyclonal or monoclonal antibodies. Such antibodies can beused in diagnostic methods and kits to detect or quantify the peptide ofthe invention, or peptides related thereto, in a body fluid or tissue.Results from these tests could be used to diagnose or determine theprognostic relevance of such peptides.

The use of the peptides of the present invention to generate monoclonalantibodies in animals such as the mouse, rabbit or sheep, followstechniques well known in the art. If desired, the antibodies can then beused to make anti-idiotype antibodies which in turn can be humanized asis known in the art to prevent immunological responses. The humanizedantibodies can be used to inhibit angiogenesis or to make kits to detectthe receptor as described herein.

For the production of polyclonal antisera in rabbits, sheep, goats orother animals the peptides of the invention are coupled, for examplethrough lysine residues, to purified bovine serum albumin usingglutaraldehyde. The efficiency of this reaction may be determined bymeasuring the incorporation of radiolabeled peptide. Unreactedglutaraldehyde and peptide may be separated by dialysis and theconjugate stored for subsequent use.

Serum samples from generation of polyclonal antisera or media samplesfrom production of monoclonal antisera may be analyzed for determinationof antibody titer and in particular, for the determination of high titerantisera Subsequently, the highest titer antisera may be tested toestablish the following: a) optimal antiserum dilution for highestspecific binding of the antigen and lowest non-specific binding, b)ability to bind increasing amounts of peptide in a standard displacementcurve, c) potential cross-reactivity with immunologically-relatedpeptides and proteins (including plasminogen, TSP-1, and TSP-1 ofrelated species), and d) ability to detect the peptide of the inventionin extracts of plasma, urine, tissues, and in cell culture media.

Titer may be established through several means known in the art, such asby dot blot and density analysis, and also by precipitation ofradiolabeled peptide-antibody complexes using protein A, secondaryantisera, cold ethanol or charcoal-dextran followed by activitymeasurement with a gamma counter. If desired, the highest titer antiseramay be purified on affinity columns. For example, the peptides of theinvention may be coupled to a commercially available resin and used toform an affinity column. Antiserum samples may then be passed throughthe column so that antibodies to the peptides of the invention bind (viathe peptide) to the column. These bound antibodies are subsequentlyeluted, collected and evaluated for determination of titer andspecificity.

Kits for measurement of the compounds of the invention are alsocontemplated as part of the present invention. Antisera that possess thehighest titer and specificity and can detect the peptides of theinvention in extracts of plasma, urine, tissues, and in cell culturemedia may be used to establish assay kits for rapid, reliable,sensitive, and specific measurement and localization of peptides of theinvention. These assay kits may employ (but are not limited to) thefollowing techniques: competitive and non-competitive assays,radioimmunoassay (RIA), bioluminescence and chemiluminescence assays,fluorometric assays, sandwich assays, immunoradiometric assays, dotblots, enzyme linked assays including ELISA, microtiter plates, antibodycoated strips or dipsticks for rapid monitoring of urine or blood, andimmunocytochemistry. For each kit the range, sensitivity, precision,reliability, specificity and reproducibility of the assay areestablished by means well known to those skilled in the art.

The above described assay kit would provide instructions, antiserum, oneor more peptides of the invention, and possibly radiolabeled peptides ofthe invention and/or reagents for precipitation of boundpeptide/antibody complexes. Such a kit would be useful for themeasurement of the peptide of the invention in biological fluids andtissue extracts of animals and humans with and without tumors, as iswell known in the art.

Another kit may be used to visualize or localize the peptide of theinvention in tissues and cells. Immunohistochemistry techniques andkits, for example, which employ such techniques are well known to thoseof ordinary skill in the art. Such a kit provides antisera to thepeptide of the invention, and possibly blocking serum and secondaryantiserum linked to a fluorescent molecule such as fluoresceinisothiocyanate, or to some other reagent used to visualize the primaryantiserum. Using this methodology, biopsied tumors may be examined forsites of peptide production or for sites of the peptide receptor.Alternatively, a kit may supply radiolabeled nucleic acids for use in insitu hybridization to probe for messenger RNA which encodes the compoundof the invention.

Synthesis of the Peptides

The polypeptides of the present invention may be synthesized by anytechniques that are known to those skilled in the art. For solid phasepeptide synthesis, a summary of the many techniques may be found in J.M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, W.H. FreemanCo. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins andPeptides, vol. 2, p. 46, Academic Press (New York), 1973. For classicalsolution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1,Acacemic Press (New York), 1965.

Reagents, resins, amino acids, and amino acid derivatives arecommercially available and can be purchased from Chem-ImpexInternational, Inc. (Wood Dale, Ill., U.S.A.) or Calbiochem-NovabiochemCorp. (San Diego, Calif., U.S.A.) unless otherwise noted herein.

In general, these methods comprise the sequential addition of one ormore amino acids or suitably protected amino acids to a growing peptidechain. Normally, either the amino or carboxyl group of the first aminoacid is protected by a suitable protecting group. The protected orderivatized amino acid can then be either attached to an inert solidsupport or utilized in solution by adding the next amino acid in thesequence having the complimentary (amino or carboxyl) group suitablyprotected, under conditions suitable for forming the amide linkage. Theprotecting group is then removed from this newly added amino acidresidue and the next amino acid (suitably protected) is then added, andso forth. After all the desired amino acids have been linked in theproper sequence, any remaining protecting groups (and any solid support)are removed sequentially or concurrently, to afford the finalpolypeptide. By simple modification of this general procedure, it ispossible to add more than one amino acid at a time to a growing chain,for example, by coupling (under conditions which do not racemize chiralcenters) a protected tripeptide with a properly protected dipeptide toform, after deprotection, a pentapeptide.

A particularly preferred method of preparing compounds of the presentinvention involves solid phase peptide synthesis.

In this particularly preferred method the alpha-amino function isprotected by an acid or base sensitive group. Such protecting groupsshould have the properties of being stable to the conditions of peptidelinkage formation, while being readily removable without destruction ofthe growing peptide chain or racemization of any of the chiral centerscontained therein. Suitable protecting groups are9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc),benzyloxycarbonyl (Cbz), biphenylisopropyl-oxycarbonyl,t-amyloxycarbonyl, isobornyloxycarbonyl,(α,α)-dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl,2-cyano-t-butyloxycarbonyl, and the like. The9-fluorenylmethyloxycarbonyl (Fmoc) protecting group is preferred.

Particularly preferred side chain protecting groups are, for side chainamino groups as in lysine and arginine:2,2,5,7,8-pentamethylchroman-6-sulfonyl (pmc), nitro, p-toluenesulfonyl,4-methoxybenzenesulfonyl, Cbz, Boc, and adamantyloxycarbonyl; fortyrosine: benzyl, o-bromobenzyloxycarbonyl, 2,6-dichlorobenzyl,isopropyl, t-butyl (t-Bu), cyclohexyl, cyclopenyl and acetyl (Ac); forserine: 1-butyl, benzyl and tetrahydropyranyl; for histidine: trityl,benzyl, Cbz, p-toluenesulfonyl and 2,4-dinitrophenyl; for tryptophan:formyl and Boc.

In the solid phase peptide synthesis method, the C-terminal amino acidis attached to a suitable solid support or resin. Suitable solidsupports useful for the above synthesis are those materials which areinert to the reagents and reaction conditions of the stepwisecondensation-deprotection reactions, as well as being insoluble in themedia used. The preferred solid support for synthesis of C-terminalcarboxy peptides is 4-hydroxymethylphenoxymethyl-copoly(styrene-1%divinylbenzene). The preferred solid support for C-terminal amidepeptides is4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamidoethyl resinavailable from Applied Biosystems.

The C-terminal amino acid is coupled to the resin by means ofN,N′-dicyclohexylcarbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC)or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU), with or without 4-dimethylaminopyridine (DMAP),1-hydroxybenzotriazole (HOBT),benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate(BOP) or bis(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCld), mediatedcoupling for from about 1 to about 24 hours at a temperature of between10° and 50° C. in a solvent such as dichloromethane or DMF. When thesolid support is4-(2′,4′-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamidoethyl resin,the Fmoc group is cleaved with a secondary amine, preferably piperidine,prior to coupling with the C-terminal amino acid as described above. Thepreferred method for coupling to the deprotected4(2,′4′-dimethoxyphenyl-Fmoc-aminomethylphenoxyacetamidoethyl resin isis O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU, 1 equiv.) and 1-hydroxybenzotriazole (HOBT, 1 equiv.) in DMF.

The coupling of successive protected amino acids can be carried out inan automatic polypeptide synthesizer as is well known in the art. In apreferred embodiment, the α-amino function in the amino acids of thegrowing peptide chain are protected with Fmoc. The removal of the Fmocprotecting group from the N-terminal side of the growing peptide isaccomplished by treatment with a secondary amine, preferably piperidine.Each protected amino acid is then introduced in about 3-fold molarexcess and the coupling is preferably carried out in DMF. The couplingagent is normallyO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU, 1 equiv.) and 1-hydroxy-benzotriazole (HOBT, 1 equiv.).

At the end of the solid phase synthesis, the polypeptide is removed fromthe resin and deprotected, either in succession or in a singleoperation. Removal of the polypeptide and deprotection can beaccomplished in a single operation by treating the resin-boundpolypeptide with a cleavage reagent, for example thianisole, water,ethanedithiol and trifluoroacetic acid.

In cases wherein the C-terminus of the polypeptide is an alkylamide, theresin is cleaved by aminolysis with an alkylamine. Alternatively, thepeptide may be removed by transesterification, e.g. with methanol,followed by aminolysis or by direct transamidation. The protectedpeptide may be purified at this point or taken to the next stepdirectly. The removal of the side chain protecting groups isaccomplished using the cleavage cocktail described above.

The fully deprotected peptide is purified by a sequence ofchromatographic steps employing any or all of the following types: ionexchange on a weakly basic resin in the acetate form; hydrophobicadsorption chromatography on underivitized polystyrenedivinylbenzene(for example, AMBERLITE® XAD); silica gel adsorption chromatography; ionexchange chromatography on carboxymethylcellulose; partitionchromatography, e.g. on SEPHADEX® G-25, LH-20 or countercurrentdistribution; high performance liquid chromatography (HPLC), especiallyreverse-phase HPLC on octyl- or octadecylsilyl-silica bonded phasecolumn packing.

The following examples will serve to further illustrate the preparationof the novel compounds of the invention.

Preparation of the Cleavage Reagent

The cleavage reagent (2 mL) is prepared by mixing, in the followingorder, thioanisole (100 μL), water (50 μL), ethanedithiol (50 μL) andtrifluoroacetic acid (1.8 mL). The freshly-prepared mixture is cooled to−5° C. to −10° C. and used as described below.

Cleavage and Deprotection Procedure

A mixture of resin-bound polypeptide and cleavage reagent is stirred at0° C. for 10-15 minutes and then at ambient temperature for a further1.75 hours. The amount of time is increased by 0.5 hours for eachadditional arginine up to a total of three hours. The amount of cleavagereagent used is determined using the following formula:

weight of resin (mg) amount of cleavage reagent (μL)  0-10 100 10-25 20025-50 400  50-100 700 100-200 1200

The resin is then filtered off and rinsed with neat trifluoroaceticacid. The filtrate is then added in 0.5 mL portions to a centrifuge tubecontaining about 8 mL of cold diethyl ether. The suspension is thencentrifuged and the supernatant is decanted off. The pellet isre-suspended in about 8 mL of ether, another 0.5 mL of the filtrate isadded, and the process is repeated until all of the peptide isprecipitated. The precipitated filtrate is then washed with ether, driedand lyophilized.

If the peptide does not precipitate upon addition to ether, the mixtureis shaken with aqueous 30% acetic acid. The organic phase is thenextracted twice with aqueous 30% acetic acid and the combined aqueousextracts are lyophilized.

EXAMPLE 1 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

In the peptide synthesis column position of a Perkin Elmer/AppliedBiosynthesis SYNERGY® peptide synthesizer is placed an Pro(2-CITrt)peptide synthesis column (25 μM amino acid; Nova Biochem). Amino acidsare added sequentially according to the following synthetic cycle:

(1) Solvating the resin using DMF for about 5 minutes;

(2) Washing with DMF for about 5 minutes;

(3) Activating the incoming Fmoc protected amino acid (75 μM) using a0.2 M solution of HBTU (75 μM) and HOBT (75 μM) in DMSO-NMP(N-methylpyrrolidone);

(4) Coupling using a solution in DMF of the activated Fmoc protectedamino acid prepared in step 3 above for about 30 minutes;

(5) Washing with DMF for 5 minutes; and

(6) For peptides capped with acetyl at the N-terminus, substitutingacetic acid (87 μM) for an Fmoc protected amino acid and using 87 μMeach of HBTU and HOBT.

(7) For peptides capped with ethylamide at the C-terminus, adding DMF tothe resin followed by ByProp (1.1 equivalents) and ethylamine (20equivalents) in THF.

The amino acids were coupled to the resin in the following order usingthe conditions indicated.

# Amino Acid Coupling 1. Fmoc-Arg(Pmc) 30 minutes 2. Fmoc-Ile 30 minutes3. Fmoc-Nva 30 minutes 4. Fmoc-Thr(t-Bu) 30 minutes 5. Fmoc-D-Ile 30minutes 6. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes 8. Fmoc-Sar 30minutes

Upon completion of the synthesis, the resin was washed with THF forabout 5 minutes to remove DMF and shrink the resin. The resin was thengas dried with argon for about 10 minutes and nitrogen for a further 10minutes to provide the resin-bound peptide (85 mg). Cleavage anddeprotection are accomplished using the procedure described above (40 mgof dry resin-bound peptide, 700 μL of cleavage reagent, cleavage time2.5 hours) to give the crude peptide (14 mg). Purification by HPLC usinga 7 μm Symmetry Prep C18 column (7.8×300 mm) with solvent mixturesvarying in a gradient from 5% to 100% acetonitrile-water over a periodof 50 minutes followed by lyophilization provided the desired peptide.

The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=26.5 min (10% to 40% acetonitrile in watercontaining 0.01% of TFA, over 30 min period); MS (ESI) m/e 994 (M+H)⁺.

EXAMPLE 2 N-Ac-pyroGlu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

# Amino Acid Coupling 1. Fmoc-Arg(Pmc) 30 minutes 2. Fmoc-Ile 30 minutes3. Fmoc-Nva 30 minutes 4. Fmoc-Thr(t-Bu) 30 minutes 5. Fmoc-D-Ile 30minutes 6. Fmoc-Val 30 minutes 7. Fmoc-Gly 30 minutes 8. pyroGlu(Boc) 30minutes

The desired peptide was prepared using the conditions described forExample 1. The amino acids were coupled to the resin in the followingorder using the conditions indicated.

The pure fractions were lyophilized to yieldpyroGlu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=23.5 min (gradient of 10% to 40%acetonitrile in water containing 0.01% of TFA, over 30 min period); MS(ESI) m/e 994 (M+H)⁺.

EXAMPLE 3 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₃

The procedure described in Example 1 was used but substitutingmethylamine (2.0 M solution in THF) for ethylamine. After cleavage ofthe peptide from the resin and removal of the protecting groups thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₃ as the trifluoroacetatesalt: R_(t)=3.224 min (gradient of 20% to 95% acetonitrile in watercontaining 0.01 M NH₄Ac over 10 min period); MS (ESI) m/e 930 (M+H)⁺;Amino Acid Anal.: 1.09 Sar; 1.03 Gly; 0.98 Val; 0.98 Ile; 0.54 Thr; 1.72Nva; 1.01 Arg; 1.08 Pro.

EXAMPLE 4 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in Example 1 was used but substitutingisopropylamine for ethylamine. After cleavage of the peptide from theresin and removal of the protecting groups the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHIsopropyl as thetrifluoroacetate salt: R_(t)=3.648 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1008 (M+H)⁺; Amino Acid Anal.: 1.10 Sar; 0.99 Gly; 0.96 Val;1.88 Ile; 0.56 Thr; 1.67 Nva; 0.96 Arg; 1.09 Pro.

EXAMPLE 5N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-(1-pyrrolidine) ResinPreparation

4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin (0.5 g, 0.54 mmol/gsubstitution) was placed in a solid phase synthesis reaction vesselcontaining (9:1) DMA/acetic acid (4 mL). The mixture was shaken for 5min. The resin was drained and this process was repeated three times. Tothe swollen resin were added 10-15 grains of activated 4A molecularsieves and (9:1) DMA/acetic acid (4mL) and 10 molar equivalents of1-(2-aminoethyl)pyrrolidine. The slurry was shaken for 1 h at rt and toit was added 10 molar equivalents of sodium triacetoxyborohydride. Theslurry was shaken for 2 h at rt. The resin was drained and washed threetimes with DMA, three times with methanol, three times withdichloromethane, three times with diethyl ether and dried in vacuo at rtovernight. The dry resin was swollen in DMA (4 mL) and shaken for 5 min.This process was repeated twice.

Coupling of Fmoc-Pro

To the swollen resin in the reaction vessel were added sequentially thefollowing chemicals; DMA (4 mL), one equivalent of DIEA, a DMA solutioncontaining 3.0 equivalents of Fmoc-Pro, 3.0 equivalents of HATU, and 3.0equivalents of DIEA. The slurry was shaken overnight. The resin wasdrained and washed three times with DMA, three times with methanol,three times with dichloromethane, three times with diethyl ether anddried in vacuo at rt overnight. A small portion of the resin was used todetermine the Fmoc-Pro loading. The rest of the resin was shaken withDMA (4 mL) three times for 5 min and then for 1 h at rt with a solutionof (8:1:1) DMA/pyridine/acetic anhydride (5 mL). The resin was drainedand washed three times with DMA, three times with methanol, three timeswith dichloromethane, and three times with diethyl ether. The resin wasdried in vacuo at rt overnight and then used in the subsequent solidphase peptide synthesis.

Synthesis of Above Peptide

In the synthesis of the above peptide the amino acids, the couplingconditions and the synthetic protocol used were the identical to asthose described in Example 1. Upon completion of the synthesis thepeptide and the protecting groups were cleaved at rt using (95:5)TFA/anisole (3 mL) for 3 h. The resin was filtered and washed threetimes with methanol. The combined filtrates were concentrated in vacuoand to the residue was added diethylether. The solid precipitate wasfiltered. The crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl(1-pyrrolidine) as thebis-trifluoroacetate salt: R_(t)=4.40 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1063 (M+H)⁺; Amino Acid Anal.: 0.95 Sar; 1.0 Gly; 0.86 Val;1.63 Ile; 0.56 Thr; 1.38 Nva; 0.88 Arg; 1.07 Pro.

EXAMPLE 6N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl(1-piperidine)

The procedure described in Example 5 was used but substituting1-(2-amino-ethyl)piperidine for 1-(2-aminoethyl)pyrrolidine in thereductive alkylation step. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 100% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-(1-piperidine) as thebis-trifluoroacetate salt: R_(t)=4.437 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1077 (M+H)⁺; Amino Acid Anal.: 1.11 Sar; 1.04 Gly; 0.99 Val;1.77 Ile; 0.61 Thr; 1.61 Nva; 0.97 Arg; 1.10 Pro.

EXAMPLE 7 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHmethylcyclopropyl

The procedure described in Example 1 was used but substituting(aminoethyl)cyclopropane for 1-(2-aminoethylpyrrolidine). After cleavageof the peptide from the resin and removal of the protecting groups thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHmethylcyclopropyl as thetrifluoroacetate salt: R^(t)=3.815 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1020 (M+H)⁺; Amino Acid Anal.: 1.01 Sar; 0.96 Gly; 0.96 Val;1.66 Ile; 0.53 Thr; 1.65 Nva; 1.08 Arg; 1.09 Pro.

EXAMPLE 8N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)cyclohexyl

The procedure described in Example 5 was used but substituting(R)-1-cycloxylethylamine for 1-(2-aminoethylpyrrolidine). After cleavageof the peptide from the resin and removal of the protecting groups thecrude product was purified by C-18 column chromatography using solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure factions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)cyclohexyl as thetrifluoroacetate salt: R^(t)=5.196 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1076 (M+H)⁺; Amino Acid Anal.: 1.19 Sar; 0.99 Gly; 0.62 Val;1.47 Ile; 0.48 Thr; 1.57 Nva; 1.01 Arg; 0.83 Pro.

EXAMPLE 9

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(2-hydroxyethyl)

The procedure described in Example 5 was used but substitutingO-TBDMS-ethanolamine for 1-(2-aminoethylpyrrolidine). After cleavage ofthe peptide from the resin and removal of the protecting groups thecrude product was purified by C-18 column chromatography using solventmixture varying in a gradient of 10% to 500% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(2-hydroxyethyl) as thetrifluoroacetate salt: R_(t)=4.04 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1010 (M+H)⁺; Amino Acid Anal.: 1.04 Sar; 1.01 Gly; 0.98 Val;1.59 Ile; 0.44 Thr; 1.45 Nva; 0.99 Arg; 1.06 Pro.

EXAMPLE 10 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂

The procedure described in Example 1 was used but substitutingFmoc-Pro-Sieber amide resin for H-Pro-2CITrt resin. After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL), the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂ asthe trifluoroacetate salt: R_(t)=4.063 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 966 (M+H)⁺; Amino Acid Anal.: 0.87 Sar; 0.98 Gly; 0.94 Val;1.73 Ile; 0.47 Thr; 1.35 Nva; 1.02 Arg; 1.05 Pro.

EXAMPLE 11

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃

The procedure described in Example 5 was used but substituting2-methoxyethylamine for 1-(2-aminoethylpyrrolidine). After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂—OCH₃ as thetrifluoroacetate salt: R_(t)=3.40 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) M/e 1024 (M+H)⁺; Amino Acid Anal.: 1.02 Sar; 1.06 Gly; 0.97 Val;1.54 Ile; 0.47 Thr; 1.81 Nva; 0.97 Arg; 1.25 Pro.

EXAMPLE 12

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂-cyclohexyl

The procedure described in Example 5 was used but substitutingcyclohexylethylamine for 1-(2-aminoethylpyrrolidine). After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂-cyclohexyl as thetrifluoroacetate salt: R_(t)=4.97 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1076 (M+H)⁺; Amino Acid Anal.: 0.87 Sar; 1.00 Gly; 0.88 Val;1.34 Ile; 0.44 Thr; 1.61 Nva; 1.07 Arg; 1.05 Pro.

EXAMPLE 13 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂CH₃

The procedure described in Example 1 was used but substitutingpropylamine for ethylamine. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.68 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1008 (M+H)⁺; Amino Acid Anal.: 0.94 Sar; 1.09 Gly; 0.96 Val;1.58 Ile; 0.51 Thr; 1.78 Nva; 0.96 Arg; 1.23 Pro.

EXAMPLE 14 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=22.5 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺; Amino Acid Anal.: 0.95 Sar; 0.96 Gly; 0.97 Val; 0.99Ile; 0.54 Thr; 1.66 Nva; 1.14 Arg; 1.08 Pro.

EXAMPLE 15 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Leu for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.54 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)M/e 994 (M+H)⁺; Amino Acid Anal.: 1.00 Sar; 0.93 Gly; 0.96 Val; 1.02Leu; 0.58Thr; 1.50 Nva; 0.99 Ile; 1.14 Arg; 1.08 Pro.

EXAMPLE 16 N-Ac-Sar-Gly-Val-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Ilefor Fmoc-D-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetatesalt: R_(t)=3.28 min (gradient of 10% to 30% acetonitrile in watercontaining 0.01% TFA over 30 min period); MS (ESI) m/e 994 (M+H)⁺; AminoAcid Anal.: 0.95 Sar; 0.94 Gly; 0.89 Val; 1.70 Ile; 0.52 Thr; 1.67 Nva;0.99 Ile; 1.27 Arg; 1.06 Pro.

EXAMPLE 17 N-Ac-Sar-Gly-Val-Gly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Glyfor Fmoc-D-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-Gly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as the trifluoroacetatesalt: R_(t)=2.47 min (gradient of 10% to 30% acetonitrile in watercontaining 0.01% TFA over 30 min period); MS (ESI) m/e 938 (M+H)⁺; AminoAcid Anal.:1.10 Sar; 1.94 Gly; 1.03 Val; 0.98 1 Ile; 0.54 Thr; 1.61 Nva;1.28 Arg; 1.05 Pro.

EXAMPLE 18 N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Val for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.13 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 980 (M+H)⁺; Amino Acid Anal.: 1.07 Sar; 1.0 Gly; 2.01 Val; 0.99 Ile;0.62 Thr; 1.54 Nva; 1.49 Arg; 1. I 1 Pro.

EXAMPLE 19 N-Ac-Sar-Gly-Val-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.174 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺; Amino Acid Anal.: 1.02 Sar; 0.99 Gly; 0.95 Val; 1.29Ile; 0.45 Thr; 1.52 Nva; 1.54 Arg; 1.07 Pro.

EXAMPLE 20 N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Ala for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.826 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 952 (M)⁺ and 908 (M-44)⁺.

EXAMPLE 21 N-Ac-Sar-Gly-Val-D-Lys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Lys(Boc) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Lys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.544 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1009 (M)⁺ and 965 (M-44)⁺.

EXAMPLE 22 N-Ac-Sar-Gly-Val-D-Met-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Met for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Met-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.141 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1012 (M)⁺.

EXAMPLE 23 N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Nle for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9;1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.383 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 994 (M)⁺.

EXAMPLE 24 N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.476 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1028 (M)⁺.

EXAMPLE 25 N-Ac-Sar-Gly-Val-D-Trp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Trp(Boc) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Trp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.430 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1024 (M)⁺.

EXAMPLE 26 N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Tyr(2-ClTrt) for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.964 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1045 (M)⁺.

EXAMPLE 27N-Ac-Sar-Gly-Val-D-4,4′-Biphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-4,4′-Biphenylala for Fmoc-D-Ile. After cleavage of the peptidefrom the resin and removal of raw the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-4,4′-Biphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.005 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1104 (M)⁺.

EXAMPLE 28 N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Cha for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.005 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1034 (M)⁺.

EXAMPLE 29 N-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Chg for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.377 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 977 (M)⁺.

EXAMPLE 30 N-Ac-Sar-Gly-Val-D-4-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-4-ClPhe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-4-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.674 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1018 (M)⁺.

EXAMPLE 31 N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Hphe for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.597 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1042 (M)⁺ and 998 (M-44)⁺.

EXAMPLE 32 N-Ac-Sar-Gly-Val-Dehydroleu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Dehydroleu for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-Dehydroleu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.1707 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 992 (M)⁺ and 949 (M-44)⁺.

EXAMPLE 33 N-Ac-Sar-Gly-Val-D-3-CF₃Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3-CF₃Phe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-3CF₃Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.825 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1097 (M)⁺ and 1053 (M44)⁺.

EXAMPLE 34 N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-pentaFPhe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.810 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1118 (M)⁺ and 1075 (M-44)⁺.

EXAMPLE 35 N-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3,4-diClPhe for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9 1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.911 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1100 (M+3)⁺.

EXAMPLE 36 N-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3-ClPhe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.689 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1062 (M)⁺.

EXAMPLE 37 N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-2-Thienylala for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.388 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1034 (M)⁺.

EXAMPLE 38 N-Ac-Sar-Gly-Val-D-3CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3-CNPhe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.361 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1009 (M)⁺.

EXAMPLE 39N-Ac-Sar-Gly-Val-D-3,3-Diphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3,3′-Diphenylala for Fmoc-D-Ile. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-3,3′-Diphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.778 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1104 (M)⁺.

EXAMPLE 40N-Ac-Sar-Gly-Val-D-3-Benzothienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3-Benzothienylala for Fmoc-Ile. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-3-Benzothienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.797 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1084 (M)⁺.

EXAMPLE 41 N-Ac-Sar-Gly-Val-D-3,4-diF-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-3,4diF-Phe for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-3,4-diF-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.608 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1064 (M)⁺.

EXAMPLE 42 N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-DNvafor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-DNva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.75 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺; Amino Acid Anal.: 1.08 Sar; 0.96 Gly; 0.95 Val; 1.74Ile; 0.50 Thr; 1.69 Nva; 1.26 Arg; 1.09 Pro.

EXAMPLE 43 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.047 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1023 (M+H)⁺; Amino Acid Anal.: 1.15 Sar; 0.96 Gly; 0.63 Val; 1.7Ile; 0.46 Thr; 0.65 Glu; 1.45 Arg; 1.04 Pro.

EXAMPLE 44 N-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Chafor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to ⁵⁰% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.503 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ES!)m/e 1048 (M+H)⁺; Amino Acid Anal.: 1.18 Sar; 0.94 Gly; 0.59 Val; 1.65Ile; 0.45 Thr; 0.37 Cha; 1.45 Arg; 1.06 Pro.

EXAMPLE 45 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gly-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Glyfor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gly-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.11 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 952 (M+H)⁺.

EXAMPLE 46 N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Alafor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure factions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.16 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 966 (M+H)⁺.

EXAMPLE 47 N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Valfor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.36 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺.

EXAMPLE 48 N-Ac-Sar-Gly-Val-D-Ile-Thr-Abu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Abufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Abu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.23 min. (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 980 (M+H)⁺.

EXAMPLE 49 N-Ac-Sar-Gly-Val-D-Ile-Thr-Allylgly-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Allylgly for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Allylgly-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.40 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 992 (M+H)⁺.

EXAMPLE 50 N-Ac-Sar-Gly-Val-D-Ile-Thr-Octylgly-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Octylgly for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Octylgly-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.30 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1064 (M+H)⁺.

EXAMPLE 51 N-Ac-Sar-Gly-Val-D-Ile-Thr-Met-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Metfor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Met-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.48 min (gradient of 10% to30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1027 (M+H)⁺)⁺.

EXAMPLE 52N-Cyclohexylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingcyclobexylacetic acid for acetic acid. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Cyclohexylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.11 min (gradient of 10% to ³⁰%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1076 (M+H)⁺)⁺; Amino Acid Anal.: 1.15 Sar; 0.97 Gly; 0.95 Val; 1.79Ile; 0.54 Thr; 1.66 Nva; 1.28 Arg; 1.08 Pro.

EXAMPLE 53N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting2-Me-nicotinic acid for acetic acid. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.11 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1071 (M+H)⁺; Amino Acid Anal.: 1.19 Sar; 1.01 Gly; 0.99 Val; 1.79Ile; 0.57 Thr; 1.70 Nva; 1.59 Arg; 1.17 Pro.

EXAMPLE 54 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but acylating the peptideresin (after the Fmoc-Sar coupling and deprotection) with a (1:1)succinic anhydride/pyridine mixture (2 mL) overnight. After washing theresin and cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.72 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1052 (M+H)⁺; Amino Acid Anal.: 1.16 Sar; 1.05 Gly; 0.95 Val; 1.85Ile; 0.57 Thr; 1.70 Nva; 1.59 Arg; 1.17 Pro.

EXAMPLE 55 N-Nicotinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting nicotinicacid for acetic acid at the last coupling. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Nicotinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.6 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1057 (M+H)⁺; Amino Acid Anal.: 1.03 Sar; 0.89 Gly; 0.81 Val; 1.48Ile; 0.40 Thr; 1.46 Nva; 1.07 Arg; 1.04 Pro.

EXAMPLE 56 N-Propionyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting propionicacid for acetic acid at the last coupling. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Propionyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.7 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ES)m/e 1008 (M+H)⁺; Amino Acid Anal.: 0.93 Sar; 0.97 Gly; 0.88 Val; 1.60Ile; 0.44 Thr; 1.58 Nva; 1.17 Arg; 1.10 Pro.

EXAMPLE 57 N-MeOacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingmethoxyacetic acid for acetic acid at the last coupling. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-MeOacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.45 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M+H)⁺; Amino Acid Anal.: 1.12 Sar; 1.06 Gly; 0.94 Val; 1.62Ile; 0.48 Thr; 1.91 Nva; 1.40 Arg; 1.27 Pro.

EXAMPLE 58 N-Shikimyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting shikimicacid for acetic acid at the last coupling. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Shikimyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt. R_(t)=3.0 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1108 (M+H)⁺; Amino Acid Anal.: 1.22 Sar; 1.06 Gly; 0.94 Val; 1.80Ile; 0.55 Thr; 1.70 Nva; 1.28 Arg; 1.26 Pro.

EXAMPLE 59 N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting 2-furoicacid for acetic acid at the last coupling. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.0 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1046 (M+H)⁺; Amino Acid Anal.: 1.02 Sar; 1.00 Gly; 0.99 Val; 1.66Ile; 0.45 Thr; 1.75 Nva; 1.45 Arg; 1.21 Pro.

EXAMPLE 60 N-Butyryl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting butyricacid for acetic acid at the last coupling. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Butyryl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.03 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1022 (M+H)⁺; Amino Acid Anal.: 1.13 Sar; 0.99 Gly; 1.01 Val; 1.93Ile; 0.67 Thr; 1.61 Nva; 1.45 Arg; 1.08 Pro.

EXAMPLE 61 N-(Tetrahydro-2-furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingtetrahydro-2-furoic acid for acetic acid at the last coupling. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography a solvent mixture varying in a gradient of10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractionswere lyophilized to yieldN-(tetrahydro-2furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ asthe trifluoroacetate salt: R_(t)=3.91 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1050 (M+H)⁺; Amino Acid Anal.: 1.12 Sar; 0.97 Gly; 0.88 Val; 1.41Ile; 0.42 Thr; 1.60 Nva; 1.43 Arg; 1.03 Pro.

EXAMPLE 62N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but coupling withFmoc-8-amino-3,6-dioxo-octanoic acid after the Fmoc-Sar coupling, afterremoval of the terminal Fmoc the peptide resin was coupled with aceticacid as described above. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.32 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30min period);MS (ESI)m/e 1139(M+H)⁺;Amino Acid Anal.: 1.04Sar; 1.01 Gly;0.91 Val; 1.67 Ile;0.53 Thr; 1.77 Nva; 1.39 Arg; 1.02 Pro.

EXAMPLE 63N-[6-N′-Acetyl-(CH₂)₅C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but coupling withFmoc6-amino-hexanoic acid after the Fmoc-Sar coupling, after removal ofthe terminal Fmoc the peptide resin was coupled with acetic acid asdescribed above. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-[6-N-Acetyl-(CH₂)₅C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.60 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1107 (M+H)⁺; Amino Acid Anal.: 1.13 Sar; 0.96 Gly; 0.89 Val; 1.42Ile; 0.43 Thr; 1.68 Nva; 1.44 Arg; 1.04 Pro.

EXAMPLE 64 N-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting hexanoicacid for acetic acid. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.95 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1050 (M+H)⁺; Amino Acid Anal.: 1.07 Sar; 0.93 Gly; 1.02 Val; 1.95Ile; 0.56 Thr; 1.31 Nva; 1.52 Arg; 1.05 Pro.

EXAMPLE 65N-[4-N′-Acetyl-butyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but coupling withFmoc-4-amino-butyric acid after the Fmoc-Sar coupling, after removal ofthe terminal Fmoc the peptide resin was coupled with acetic acid asdescribed above. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-[4N′Acetyl-butyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ asthe trifluoroacetate salt: R_(t)=4.09 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1079 (M+H)⁺; Amino Acid Anal.: 1.03 Gaba; 1.07 Sar; 0.93 Gly; 1.00Val; 1.90 Ile; 0.54 Thr; 1.30 Nva; 1.54 Arg; 1.06 Pro.

EXAMPLE 66 H-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but omitting the aceticacid coupling at the end. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldH-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thebistrifluoroacetate salt: R_(t)=3.65 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 952 (M+H)⁺; Amino Acid Anal.: 1.00 Sar; 1.00 Gly; 0.99 Val; 1.67Ile; 0.50 Thr; 1.76 Nva; 1.47 Arg; 1.22 Pro.

EXAMPLE 67 N-Ac-Sar-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Asn(Trt) for Fmoc-Val. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thebistrifluoroacetate salt: R_(t)=2.45 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1009 (M+H)⁺; Amino Acid Anal.: 1.05 Sar; 0.98 Gly; 0.96 Asp; 1.7Ile; 0.48 Thr; 1.54 Nva; 1.32 Arg; 1.07 Pro.

EXAMPLE 68N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-8-amino-3,6-dioxo-octanoic acid for Fmoc-Sar. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=4.12 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1068 (M+H)⁺; Amino Acid Anal.: 0.93 Gly; 1.02 Val; 1.97 Ile; 0.57Thr; 1.31 Nva; 1.54 Arg; 1.05 Pro.

EXAMPLE 69 N-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Profor Fmoc-Sar. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.30 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1020 (M+H)⁺; Amino Acid Anal.: 0.92 Gly; 0.99 Val; 1.80 Ile; 0.50Thr; 1.32 Nva; 1.53 Arg; 2.09 Pro.

EXAMPLE 70 N-Ac-Gly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Glyfor Fmoc-Sar. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Gly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.08 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 980 (M+H)⁺; Amino Acid Anal.: 1.89 Gly; 1.02 Val; 1.91 Ile; 0.52Thr; 1.35 Nva; 1.57 Arg; 1.09 Pro.

EXAMPLE 71 N-Ac-Ala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Alafor Fmoc-Sar. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Ala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.00 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺; Amino Acid Anal.: 1.01 Ala; 0.93 Gly; 1.01 Val; 1.92Ile; 0.56 Thr; 1.30 Nva; 1.51 Arg; 1.05 Pro.

EXAMPLE 72 N-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-NEtGly for Fmoc-Sar. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.24 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M+H)⁺; Amino Acid Anal.: 0.95 Gly; 1.04 Val; 1.99 Ile; 0.59Thr; 1.34 Nva; 1.50 Arg; 1.01 Pro.

EXAMPLE 73 N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but subsituting Fmoc-Leufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.348 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M+H)⁺; Amino Acid Anal.: 0.88 Sar; 0.99 Gly; 0.95 Val; 1.03Ile; 0.55 Thr; 1.12 Leu; 1.53 Arg; 1.07 Pro.

EXAMPLE 74 N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.963 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 982 (M+H)⁺; Amino Acid Anal.: 0.91 Sar; 0.97 Gly; 1.00 Val; 1.03Ile; 0.56 Thr; 0.23 Ser; 1.52 Arg; 1.08 Pro.

EXAMPLE 75 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 10 was used but substitutingFmoc-D-Ala-Sieber amide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt: R_(t)=4.117 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1037 (M+H)⁺; Amino Acid Anal.: 0.85 Sar; 0.94 Gly; 0.92 Val; 1.83Ile; 0.54 Thr; 1.18 Nva; 1.01 Arg; 1.04 Pro; 1.01 Ala.

EXAMPLE 76 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-D-Pro-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-Pro-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.20 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M+H)⁺.

EXAMPLE 77 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-AbuNHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Abu-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography a solvent mixture varying in a gradient of10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractionswere lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-AbuNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.35 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 982 (M+H)⁺.

EXAMPLE 78 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-PheNHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Phe-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Phe-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.73 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1044 (M+H)⁺.

EXAMPLE 79 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Tic-NHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Tic-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Tic-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.68 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1056 (M+H)⁺.

EXAMPLE 80 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Hyp-NHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Hyp-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Hyp-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.95 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1010 (M+H)⁺.

EXAMPLE 81 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Aib-NHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Aib-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Aib-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.25 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 982 (M+H)⁺.

EXAMPLE 82 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-Ala-NHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-D-Ala-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-Ala-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.95 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 m period); MS (ESI)m/e 968 (M+H)⁺.

EXAMPLE 83 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pip-NHCH₂CH₃

The procedure described in Example 10 was used but substitutingFmoc-Pip-Sieber ethylamide resin for Fmoc-Pro-Sieber amide resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9.1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pip-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.30 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M+H)⁺.

EXAMPLE 84 N-Ac-Sar-Gly-Val-D-Tyr(Et)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Tyr(Et) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Tyr(Et)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=6.01 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1072 (M)⁺.

EXAMPLE 85 N-Ac-Sar-Gly-Val-D-Cys(tBu)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Cys(tBu) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fictions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Cys(tBu)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.96 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1040 (M)⁺.

EXAMPLE 86 N-Ac-Sar-Gly-Val-D-Cys(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Cys(Acm) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Cys(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.12 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1044 (M)⁺.

EXAMPLE 87 N-Ac-Sar-Gly-Val-D-Tyr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Tyr(Bzl) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Tyr(Bzl)Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=6.74 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1135 (M+H)⁺.

EXAMPLE 88 N-Ac-Sar-Gly-Val-D-Ser(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Ser(Bzl) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ser(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.95 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1058 (M)⁺.

EXAMPLE 89 N-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-Ile-ArgProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-1Nal for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=6.30 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1081 (M+3)⁺.

EXAMPLE 90 N-Ac-Sar-Gly-Val-D-tButylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-tButylgly for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-tButylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.46 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 994 (M)⁺.

EXAMPLE 91 N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Orn(Boc) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.69 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 995 (M)⁺.

EXAMPLE 92 N-Ac-Sar-Gly-Val-D-Thr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Thr(Bzl) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Thr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=6.10 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1072 (M)⁺.

EXAMPLE 93 N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-2Nal for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=6.33 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS(APCI) m/e 1078 (M)⁺.

EXAMPLE 94 N-Ac-Sar-Gly-Val-D-Phe(4-Me)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe(4Me) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe(4-Me)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.654 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1042 (M)⁺.

EXAMPLE 95 N-Ac-Sar-Gly-Val-D-Phe(3,4-diMeO)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe(3,4-diMeO) for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe(3,4-diMeO)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.006 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1088 (M)⁺.

EXAMPLE 96N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe(3,4,5-triF) for Fmoc-D-Ile. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.848 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1082 (M)⁺.

EXAMPLE 97 N-Ac-Sar-Gly-Val-D-Phe(4NO₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe(4-NO₂) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe(4-NO₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.483 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1073 (M)⁺.

EXAMPLE 98 N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Pen(Trt) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.928 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1012 (M)⁺.

EXAMPLE 99 N-Ac-Sar-Gly-Val-D-Pen(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Pen(Acm) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure factions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Pen(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.415 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1083 (M)⁺.

EXAMPLE 100 N-Ac-Sar-Gly-Val-D-Pen(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Pen(Bzl) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Pen(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.124 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1102 (M)⁺.

EXAMPLE 101 N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Abu for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.533 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 966 (M)⁺.

EXAMPLE 102 N-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-Phe(4-Boc-NH₂) for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.545 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1043 (M)⁺.

EXAMPLE 103 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Alafor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.675 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 952 (M)⁺.

EXAMPLE 104 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gln-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Gln(Trt) for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gln-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.46 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1009 (M)⁺.

EXAMPLE 105 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Metfor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.219 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1012 (M)⁺.

EXAMPLE 106 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Phefor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.579 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1028 (M)⁺.

EXAMPLE 107 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Pro-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Profor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Pro-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.704 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 978 (M)⁺.

EXAMPLE 108 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ser-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Ser(tBu) for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ser-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.510 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 968 (M)⁺.

EXAMPLE 109 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Trp-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Trp(Boc) for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Trp-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.625 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1067 (M)⁺.

EXAMPLE 110 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Tyr(tBu) for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.017 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1044 (M)⁺.

EXAMPLE 111 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Nvafor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.139 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 980 (M)⁺.

EXAMPLE 112 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Asp(OtBu)OH for Fmoc-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt R_(t)=2.082 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 996 (M)⁺.

EXAMPLE 113 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Glyfor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.623 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 938 (M)⁺.

EXAMPLE 114 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Lys(Ac) for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac>Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.599 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1051 (M)⁺.

EXAMPLE 115 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Leufor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-1 8 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.403 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M)⁺.

EXAMPLE 116 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-2Nal for Fmoc-Ile. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.198 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1078 (M)⁺.

EXAMPLE 117 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-1Nal for Fmoc-Ile. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.217 min (gradient of 10% to 30%acetonitrile in water containing 0.0.1% TFA over 30 min period); MS(ESI) m/e 1078 (M)⁺.

EXAMPLE 118 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Allylgly for Fmoc-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.993 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 978 (M)⁺.

EXAMPLE 119 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Citfor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.408 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1038 (M)⁺.

EXAMPLE 120 N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Alafor Fmoc-Thr(Bu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.481 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 964 (M)⁺.

EXAMPLE 121 N-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Profor Fmoc-Thr(tBu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.621 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 990 (M)⁺.

EXAMPLE 122 N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Trp(Boc) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.378 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1079 (M)⁺.

EXAMPLE 123 N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Tyr(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.606 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1056 (M)⁺.

EXAMPLE 124 N-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Nvafor Fmoc-Thr(tBu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.870 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 992 (M)⁺.

EXAMPLE 125 N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Glyfor Fmoc-Thr(tBu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.397 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 950 (M)⁺.

EXAMPLE 126 N-Ac-Sar-Gly-Val-D-Leu-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Lys(Ac) for Fmoc-Thr(Bu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.365 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1063 (M)⁺.

EXAMPLE 127 N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-2Nal for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.992 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1090 (M)⁺.

EXAMPLE 128 N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-1Nal for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.032 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1090 (M)⁺.

EXAMPLE 129 N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Octylgly for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=5.90 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1062 (M)⁺.

EXAMPLE 130 N-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Gln(Trt) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.323 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1021 (M)⁺.

EXAMPLE 131 N-Ac-Sar-Gly-Val-D-Leu-Met-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Metfor Fmoc-Thr(tBu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TPA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Met-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.901 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺.

EXAMPLE 132 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.414 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 980 (M)⁺.

EXAMPLE 133 N-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Allylgly for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.801 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 990 (M)⁺.

EXAMPLE 134 N-Ac-Sar-Gly-Val-D-Leu-Ile-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substituting Fmoc-Ilefor Fmoc-Thr(tBu). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ile-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=4.028 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1006 (M)⁺.

EXAMPLE 135 N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-D-Thr(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Gly-Val-D-Leu-D-T-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.437 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M)⁺.

EXAMPLE 136 N-Ac-Sar-Gly-Val-D-Ile-Thr-Ile-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Ilefor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Ile-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.54 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M)⁺; Amino Acid Anal.: 1.07 Sar; 0.94 Gly; 0.91 Val; 3.02 Ile;0.47 Thr; 1.24 Arg; 1.04 Pro.

EXAMPLE 137 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Nlefor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.80 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1006 (M)⁼.

EXAMPLE 138 N-Ac-Sar-Gly-Val-D-Ile-Thr-Cit-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Citfor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to ⁵⁰% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Cit-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.83 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1052 (M)⁺; Acid Anal.: 1.05 Sar; 1.00 Gly; 1.00 Val; 2.13 Ile; 0.65Thr; 1.11 Cit; 1.49 Arg; 1.10 Pro.

EXAMPLE 139 N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O₂)-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Met(O₂) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O₂)-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.701 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1058 (M)⁺; Acid Anal.: 1.36 Sar; 0.94 Gly; 0.62 Val; 2.06 Ile; 0.13Thr; 0.66 Met(O2); 1.50 Arg; 0.68 Pro.

EXAMPLE 140 N-Ac-Sar-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Arg(Pmc) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=0.54 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1049 (M)⁺; Acid Anal.: 0.92 Sar; 0.74 Gly; 0.86 Val; 2.00 Ile; 0.49Thr; 2.67 Arg; 1.00 Pro.

EXAMPLE 141 N-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Tyr(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.048 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1058 (M)⁺; Acid Anal.: 0.88 Sar; 0.99 Gly; 0.97 Val; 1.97 Ile; 0.52Thr; 0.92 Tyr; 1.58Arg; 1.08 Pro.

EXAMPLE 142 N-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Glu(OtBu)-OH for Fmoc-Nva. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.348 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺; Acid Anal.: 1.05 Sar; 1.024 Gly; 0.94 Val; 2.67 Ile; 0.47Thr; 0.94 Glu; 2.20 Arg; 1.09 Pro.

EXAMPLE 143 N-Ac-Sar-Gly-Val-D-Ile-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Lys(Ac) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.744 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1065 (M)⁺; Acid Anal.: 1.03 Sar; 0.99 Gly; 0.95 Val; 2.04 Ile; 0.66Thr; 1.05 Lys; 1.41 Arg; 1.02 Pro.

EXAMPLE 144 N-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH2CH₃

The procedure described in Example 1 was used but substitutingFmoc-Propargylgly for Fmoc-Nva. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt; R_(t)=3.003 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 990 (M)⁺; Acid Anal.: 1.05 Sar; 1.00 Gly; 0.93 Val; 2.10 Ile; 0.54Thr; 1.71 Arg; 0.97 Pro.

EXAMPLE 145 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-D-alloIle for Fmoc-D-Ile and Fmoc-Gln(Trt) for Fmoc-Nva. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.704 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1023 (M)⁺; Acid Anal.: 0.93 Sar; 0.94 Gly; 0.94 Val; 2.10 Ile; 0.51Thr; 0.87 Glu; 1.45 Arg; 1.03 Pro.

EXAMPLE 146 N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 was used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.685 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1023 (M)⁺; Acid Anal.: 0.98 Sar; 0.74 Gly; 0.95 Val; 1.04 Ile; 0.49Thr; 1.04 Leu; 0.94 Glu; 1.63 Arg; 0.97 Pro.

EXAMPLE 147 N-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 65 was used but substitutingFmoc-beta-alanine for Fmoc-4-amino-butyric acid. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.92 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1065 (M)⁺; Acid Anal.: 0.99 Sar; 0.99 Gly; 1.00 Val; 1.86Ile; 0.49Thr; 1.07 Nva; 1.51 Arg; 1.02 Pro.

EXAMPLE 148 N-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 60 was used but substitutingphenylacetic acid for butyric acid. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.83 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1070 (M)⁺; Acid Anal.: 1.04 Sar; 0.979 Gly; 1.01 Val; 1.90 Ile; 0.59Thr; 1.09 Nva; 1.53 Arg; 1.03 Pro.

EXAMPLE 149 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-Azagly-NH₂

To a solution of N-Ac-Sar-Gly-Val-D-Ile-Thr(tBu)-Nva-Ile-Arg(Pmc)-Pro-OH(0.1288 g) in DMF was added semicarbazide hydrochloride (0.222 g)followed by DIEA (0.346 ml) and PyBrop (0.0513 g). The solution wasstirred at rt for 36 hr. The solvent was removed in vacuo and theresidue was treated with diethyl ether. The solid was filtered and thentreated with (9:1) TFA/anisole (3 mL) at rt for 4 hr. The solvent wasagain removed in vacuo and the residue was treated with diethyl ether.The precipitate was filtered to give the crude product as a solid. Thiswas purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.01%TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-Azagly-NH₂ as thetrifluoroacetate salt: R_(t)=2.67 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺; Acid Anal.: 0.99 Sar; 0.98 Gly; 1.00 Val; 2.13 Ile; 0.56Thr; 1.09 Nva; 0.92 Arg; 1.02 Pro.

EXAMPLE 150 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Sar-NHCH₂CH₃

The procedure described in Example 76 was used but substitutingFmoc-Sar-Sieber ethylamide resin for Fmoc-D-Pro-Sieber ethylamide resin.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Sar-NHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.93 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 968 (M)⁺; Acid Anal.: 1.96 Sar; 0.96 Gly; 0.98 Val; 2.07 Ile; 0.55Thr; 1.05 Nva; 1.49 Arg.

EXAMPLE 151 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂

The procedure described in Example 75 was used but substitutingFmoc-Ser(tBu)-Sieber amide resin for Fmoc-D-Ala-Sieber amide resin.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂ as thetrifluoroacetate salt: R_(t)=2.65 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1053 (M)⁺; Acid Anal.: 0.99 Sar; 0.95 Gly; 1.00 Val; 1.96 Ile; 0.57Thr; 1.12 Nva; 1.03 Arg; 1.03 Pro; 0.27 Ser.

EXAMPLE 152 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 54 was used but substitutingFmoc-D-Leu for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.85 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1052 (M)⁺; Acid Anal.: 1.01 Sar; 0.93 Gly; 0.95Val; 1.16 Leu; 1.10Ile; 0.51 Thr; 1.04 Nva; 1.67 Arg; 0.96 Pro.

EXAMPLE 153 N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Alafor Fmoc-Gly. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.056 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M)⁺; Acid Anal.: 1.32 Sar; 0.96 Ala; 0.94 Val; 2.10 Ile; 0.52Thr; 0.98 Nva; 1.65 Arg; 1.01 Pro.

EXAMPLE 154 N-Ac-Sar-Leu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Leufor Fmoc-Gly. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Leu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.628 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1050 (M)⁺.

EXAMPLE 155 N-Ac-Sar-Ser-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Ser(tBu) for Fmoc-Gly. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Ser-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.955 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺.

EXAMPLE 156 N-Ac-Sar-Phe-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Phefor Fmoc-Gly. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Phe-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.83 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1084 (M)⁺.

EXAMPLE 157 N-Ac-Sar-Glu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Glu(OtBu)-OH for Fmoc-Gly. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Glu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.08 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1065 (M)⁺.

EXAMPLE 158 N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Profor Fmoc-Gly and Fmoc-D-Leu for Fmoc-D-Ile. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.343 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1034 (M)⁺.

EXAMPLE 159 N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Asn(Trt) for Fmoc-Gly and Fmoc-D-Leu for Fmoc-D-Ile. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.112 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1051 (M)⁺.

EXAMPLE 160 N-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Asp(OtBu)OH for Fmoc-Gly and Fmoc-D-Leu for Fmoc-D-Ile. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product was purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.9113 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1052 (M)⁺.

EXAMPLE 161 N-Ac-Asn-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Asn(Trt) for Fmoc-Sar and Fmoc-D-Leu for Pmoc-D-Ile. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Asn-Gly-Val-D-Leu-r-Nva-Ile-Arg-ProNHCH₂CH₃ asthe trifluoroacetate salt: R_(t)=3.06 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1037 (M)⁺.

EXAMPLE 162 N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Gln(Trt) for Fmoc-Sar and Fmoc-D-Leu for Fmoc-D-Ile. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.10 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1051 (M)⁺.

EXAMPLE 163

N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Ser(tBu) for Fmoc-Sar and Fmoc-D-Leu for Fmoc-D-Ile. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.15 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1010 (M)⁺.

EXAMPLE 164 N-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH₃

The procedure described in Example 1 was used but substituting Fmoc-Citfor Fmoc-Sar. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.97 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1080 (M)⁺.

EXAMPLE 165 N-Ac-Glu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH3

The procedure described in Example 1 was used but substitutingFmoc-Glu(tBu)-OH for Fmoc-Sar. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Glu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.69 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1052 (M)⁺.

EXAMPLE 166 N-Ac-Gaba-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH3

The procedure described in Example 1 was used but substitutingFmoc-gamma-aminobutyric acid for Fmoc-Sar. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure factions werelyophilized to yield N-Ac-Gaba-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.17 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M)⁺.

EXAMPLE 167 N-Ac-Bala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-beta-alanine for Fmoc-Sar. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Bala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.14 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M)⁺.

EXAMPLE 168 N-Ac-Gln-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Gln(Trt) for Fmoc-Sar. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Gln-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.00 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1051 (M)⁺.

EXAMPLE 169 N-Ac-Sar-Gly-Gly-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Glyfor Fmoc-Val. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Gly-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH3 as thetrifluoroacetate salt: R_(t)=2.46 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 952 (M)⁺.

EXAMPLE 170 N-Ac-Sar-Gly-Glu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Glu(OtBu) OH for Fmoc-Val. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Glu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=1.74 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺.

EXAMPLE 171 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 was used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂(CH₃)₂ as thetrifluoroacetate salt: R_(t)=2.80 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1037 (M)⁺; Acid Anal.: 0.98 Sar; 0.94 Gly; 0.97 Val; 2.23 Ile; 0.51Thr; 0.90 Glu; 1.16 Arg; 1.03 Pro.

EXAMPLE 172 N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 was used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Gln(Trt) for Fmoc-Nva. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure factions werelyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt: R_(t)=2.90 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1037 (M)⁺; Acid Anal.: 1.05 Sar; 0.97 Gly; 0.99 Val; 1.30 Leu 1.11Ile; 0.52 Thr; 0.89Glu; 1.20 Arg; 1.04 Pro.

EXAMPLE 173 H-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 172 was used but omitting the lastcoupling with acetic acid. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldH-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt: R_(t)=2.55 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 981 (M)⁺; Acid Anal.: 1.02 Sar; 0.93 Gly; 1.02 Val; 1.05 Leu; 1.02Ile; 0.55 Thr; 0.84 Gln; 1.31 Arg; 1.03 Pro.

EXAMPLE 174 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 54 was used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.02 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1081 (M)⁺; Acid Anal.: 1.00 Sar; 0.94 Gly; 1.00 Val; 2.00 Ile; 0.52Thr; 0.87 Gln; 1.37 Arg; 1.05 Pro.

EXAMPLE 175 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 174 was used but substitutingFmoc-D-Leu for Fmoc-D-Ile. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.284 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1081 (M)³⁰ .

EXAMPLE 176 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 was used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Gln(Trt) for Fmoc-Nva. Following thecoupling with Fmoc-Sar and protection the resin was treated withsuccinic anhydride/pyridine as described in example 54. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile/water containing 0.01% TFA. The pure fractions werelyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt: R_(t)=2.56 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1095 (M)⁺; Acid Anal.: 0.95 Sar; 0.94 Gly; 1.02 Val; 1.02 Leu; 1.05Ile; 0.56 Thr; 0.86 Gln; 1.00 Arg; 1.07 Pro.

EXAMPLE 177 N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 146 was used but substitutingFmoc-Asp(OtBu)OH for Fmoc-Gln(Trt). After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product was purified by C-18 column chromatographyusing a solvent mixture varying in a gradient of 10% to 50%acetonitrile-water containing 0.01% TFA. The pure factions werelyophilized to yield N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=2.53 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1010 (M)⁺; Acid Anal.: 1.00 Sar; 0.95 Gly; 1.01 Val; 1.02 Leu; 1.00Ile; 0.56 Thr; 0.99 Asp; 1.43 Arg; 1.03 Pro.

EXAMPLE 178 N-Ac-Sar-Gly-Val-D-Ile-Thr-Asp-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 142 was used but substitutingFmoc-Asp(OtBu)-OH for Fmoc-Glu(OtBu)OH. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Sar-Gly-Val-D-Ile-Thr-Asp-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=2.455 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1010 (M)⁺.

EXAMPLE 179 N-Ac-Sar-Gly-Val-D-Ile-Thr-Asn-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 43 was used but substitutingFmoc-Asn(Trt) for Fmoc-Gln(Trt). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Vat-D-Ile-Thr-Asn-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.68 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1009 (M)⁺.

EXAMPLE 180 N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O)-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 139 was used but substitutingFmoc-Met(O) for Fmoc-Met(O₂). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Tr-Met(O)-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.713 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1042 (M)⁺.

EXAMPLE 181 N-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 146 was used but substitutingFmoc-Asn(Trt) for Fmoc-Gln(Trt). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-Ile-&g-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.752 min (gradient of 100% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1009 (M)⁺.

EXAMPLE 182

The procedure described in Example 1 is used but separately substitutingin the syntheses Fmoc-D-Ile with the following amino acids:Fmoc-D-Thr(tBu), Fmoc-D-Ser(tBu), Fmoc-D-Hser(tBu), Fmoc-D-Gln(Trt),Fmoc-D-Asn(Trt), Fmoc-D-Cit, Fmoc-D-Hcit, Fmoc-D-Hle,Fmoc-D-Neopentylgly. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions arm lyophilized to yield thetrifluoroacetate salt of the following peptides:

N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Cit-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Hcit-Thr-Nva-Ile-Arg-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Hle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 183 N-Ac-Sar-Gly-Val-D-Ile-Thr-Phe(4CONH₂)-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 43 is used but substitutingFmoc-Phe[4-CONH(Trt)] for Fmoc-Gln(Trt). After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Phe(4-CONH₂)Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 184 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-His(Boc) for Fmoc-Arg(Pmc). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃.

EXAMPLE 185 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Isp)-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Lys(N-epsilon-Isp,N-epsilon-Boc) for Fmoc-Arg(Pmc). After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Isp)ProNHCH₂CH₃.

EXAMPLE 186

The procedure described in Example 185 is used but separatelysubstituting in each synthesis Fmoc-Lys(N-epsilon-nicotinyl),Fmoc-Orn(N-delta-nicotinyl), Fmoc-Orn(N-delta-Isp,N-epsilon-Boc),Fmoc-Phe(4-N-Isp,4-N-Boc), Fmoc-Cha(4N-Isp,4-N-Boc) instead ofFmoc-Lys(N-epsilon.Isp,N-epsilon-Boc). After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude products are purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides:

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Nic)-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(Nic)ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(Isp)-ProNHCH₂CH_(3,)

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-NIsp)-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cha(4-NIsp)ProNHCH₂CH₃.

EXAMPLE 187 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Harg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Harg(Pmc) for Fmoc-Arg(Pmc). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Harg-ProNHCH₂CH₃.

EXAMPLE 188 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Norarg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Norarg(N,N-bis-Boc) for Fmoc-Arg(Pmc). After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Norarg-ProNHCH₂CH₃.

EXAMPLE 189 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cit-ProNHCH₂CH₃

The procedure described in Example 1 is used but substituting Fmoc-Citfor Fmoc-Arg(Pmc). After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cit-ProNHCH₂CH₃.

EXAMPLE 190 N-Ac-Sar-Gly-Val-Ile-Thr-Nva-Ile-Lys-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Lys(Boc) for Fmoc-Arg(Pmc). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys-ProNHCH₂CH₃.

EXAMPLE 191 N-Ac-Sar-Gly-Val-D-Ile-Phe(4-CH₂OH)Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Phe[4-CH₂O(Trt)] for Fmoc-Thr(Trt). After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Phe(4CH₂OH)-Nva-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 192 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4guanidino)ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Phe(4-bis-Boc-guanidino) for Fmoc-Arg(Pmc). After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% toS50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-guanidino)-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.423 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1042 (M+H)⁺.

EXAMPLE 193N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Aminopyrimidinylbutanoyl-ProNHCH₂CH₃.

The procedure described in Example 1 was used but substitutingFmoc-2-amino4-[(2-amino)pyrimidinyl]butanoic acid for Fmoc-Arg(Pmc).After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product waspurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Aminopyrimidinylbutanoyl-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.303 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1016 (M+H)⁺.

EXAMPLE 194N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-CH₂NHIsp)-ProNHCH₂CH₃

The procedure described in Example 1 is used but substituting Fmoc-Phe(4-CH₂NIsp-Boc) for Fmoc-Arg(Pmc). After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-CH₂NHIsp)-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 195N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Gly[4-Pip(N-amidino)]-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Gly4-piperidinyl[N-amidino(BOC)₂] for Fmoc-Arg(Pmc). After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Gly(4Pip-amidino)-ProNHCH₂CH₃ as the trifluoroacetate salt.

EXAMPLE 196N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala[4-Pip(N-amidino)]-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Ala-[4-piperidinyl-(N′,N″-bis-Boc-amidino)] for Fmoc-Arg(Pmc).After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala[4-Pip(N-amidino)]-Pro-NHCH₂CH₃ asthe trifluoroacetate salt.

EXAMPLE 197N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-guanidino)ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Ala-[3bis-Boc)guanidino] for Fmoc-Arg(Pmc). After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-guanidino)-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 198N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-pyrrolidinylamidino)-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Ala[3-pyrroli-dinyl-(2-N,N′-bis-Boc-amidino)] for Fmoc-Arg(Pmc).After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala-(3-pyrrolidinyl-amidino)-ProNHCH₂CH₃as the trifluoroacetate salt.

EXAMPLE 199N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(2-imidazo)-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Orn-[N-2-(1-Boc)imidazolinyl] for Fmoc-Arg(Pmc). After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(2-imidazo)-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 200 N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 54 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Nva Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 201 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 54 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 500% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 202 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva and, after the coupling with Fmoc-Sar;acylating the peptide resin with succinic anhydride as described inExample 54. After cleavage of the peptide from the resin and removal ofthe protecting groups using (9:1) TFA/anisole (3 mL) the crude productis A purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.01%TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 203 N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 201 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mid) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 204N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 202 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 205 N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 175 is used but substitutingFmoc-D-alloIle for Fmoc-D-Leu. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 206 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 205 is used but substitutingFmoc-D-Ile for Fmoc-D-alloIle. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 207 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions arc lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-D-Ala-NH₂ as thetrifluoroacetate salt.

EXAMPLE 208 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt.

EXAMPLE 209 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 210 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt.

EXAMPLE 211 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 209 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 212 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 210 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt.

EXAMPLE 213 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂

The procedure described in Example 75 is used but substitutingFmoc-Sar-Seiberamide-resin for Fmoc-D-Ala-Seiberamide-resin. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂ as thetrifluoroacetate salt.

EXAMPLE 214 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-SarNH₂

The procedure described in Example 213 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-SarNH₂ as thetrifluoroacetate salt.

EXAMPLE 215 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-SarNH₂

The procedure described in Example 213 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-SarNH₂ as thetrifluoroacetate salt.

EXAMPLE 216 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-SarNH₂

The procedure described in Example 215 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-SarNH2 as thetrifluoroacetate salt.

EXAMPLE 217 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 207 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 218 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 208 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt.

EXAMPLE 219 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 15 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 220 N-Ac-Sar-Gly-Val-D-Ile-Thr-Orn(Ac)-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Orn(Ac) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Orn(Ac)-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 221 N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂

The procedure described in Example 149 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂ as thetrifluoroacetate salt.

EXAMPLE 222 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂

The procedure described in Example 149 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂ as thetrifluoroacetate salt.

EXAMPLE 223 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂

The procedure described in Example 222 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-AzaglyNH2 as thetrifluoroacetate salt.

EXAMPLE 224N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 61 is used but substitutingtetrahydro2-furoic acid for acetic acid. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ asthe trifluoroacetate salt.

EXAMPLE 225N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 61 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 226N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 225 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ asthe trifluoroacetate salt.

EXAMPLE 227N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 209 is used but substitutingtetrahydro-2-furoic acid for acetic acid. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 228N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 227 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂ asthe trifluoroacetate salt.

EXAMPLE 229N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile, Fmoc-Gln(Trt) for Fmoc-Nva andtetrahydro-2-furoic acid for acetic acid. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂ asthe trifluoroacetate salt.

EXAMPLE 230

The procedures described in examples 224, 225, 226, 227, 228, and 229are used but substituting N-acetyl-6-aminocaproic acid (6-Ac-Aca)instead of tetrahydro-2furoic acid. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, and

N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 231

The procedures described in examples 224, 225, 226, 227, 228, and 229are used but substituting N-acetyl-4-aminobutyric acid (4-Ac-Gaba)instead of tetrahydro-2-furoic acid. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, and

N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 232

The procedures described in examples 224, 225, 226, 227, 228, and 229are used but substituting 2-furoic acid instead of tetrahydro-2-furoicacid. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-(42-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, and

N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 233

The procedures described in examples 224, 225, 226, 227, 228, and 229are used but substituting shikimic acid instead of tetrahydro-2-furoicacid. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-(4Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, and

N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 234

The procedures described in examples 224, 225, 226, 227, 228, and 229are used but substituting 2-methyl-nicotinic acid instead oftetrahydro2-furoic acid. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides:

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,and

N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 235 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile and Fmoc-Leu for Fmoc-Nva. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

Example 236 N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH(CH₃)₂

The procedure described in example 4 is used but substituting Fmoc-Leufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH(CH₃)₂ as thetrifluoroacetate salt.

EXAMPLE 237 N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 73 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 238 N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substituting Fmoc-Leufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 239 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substituting Fmoc-Leufor Fmoc-Nva and acylating with succinic anhydride after the couplingwith Fmoc-Sar and deprotection as described in Example 54. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 240 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg- ProNHCH₂CH₃

The procedure described in Example 206 is used but substituting Fmoc-Leufor Fmoc-Gln(Trt) and acylating with succinic anhydride after thecoupling with Fmoc-Sar and deprotection as described in Example 54.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 241

The procedures described in Examples 201, 202 and 203 are used butsubstituting Fmoc-Leu instead of Fmoc-Gln(Trt). After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides:

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂.

EXAMPLE 242 N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-AzaglyNH₂

The procedure described in Example 149 is used but substituting Fmoc-Leufor Fmoc-Nva and acylating with succinic anhydride after the couplingwith Fmoc-Sar and deprotection as described in Example 54. Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-AzaglyNH₂ as thetrifluoroacetate salt.

EXAMPLE 243N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHethyl-(1-pyrrolidine)

The procedure described in Example 5 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHethyl-(1-pyrrolidine) asthe trifluoroacetate salt.

EXAMPLE 244N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNH(ethyl-1-cyclohexyl)

The procedure described in Example 8 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNH(ethyl-1-cyclohexyl) asthe trifluoroacetate salt.

EXAMPLE 245N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHethyl(1-pyrrolidine)

The procedure described in Example 5 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHethyl-(1-pyrrolidine) as thetrifluoroacetate salt.

EXAMPLE 246N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl)

The procedure described in Example 8 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl) as thetrifluoroacetate salt.

EXAMPLE 247N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl)

The procedure described in Example 246 is used but acylating the peptideresin with succinic anhydride after the coupling with Fmoc-Sar anddeprotection as described in Example 54. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl)as the trifluoroacetate salt.

EXAMPLE 248

The procedures described in Examples 11 is used but substituting theappropriate protected amino acids as described in Examples 14, 43, 74,73, 54, 174, and 132 respectively. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, and

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃.

EXAMPLE 249

The procedures described in Examples 49 is used but substituting theappropriate protected amino acids as described in Examples 14,4, 75, 54and 132 respectively. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Leu-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃.

EXAMPLE 250 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-SerNH₂

The procedure described in Example 75 is used but substitutingFmoc-D-Ser(tBu)-Sieber amide resin for Fmoc-D-Ala-Sieber amide resin.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-SerNH₂ as thetrifluoroacetate salt.

EXAMPLE 251 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHOH

The procedure described in Example 149 is used but hydroxylaminehydrochloride for semicarbazide hydrochloride. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHOH asthe trifluoroacetate salt.

EXAMPLE 252 N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-D-Ile for Fmoc-D-Leu After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 253 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-D-alloIle for Fmoc-D-Leu. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 254 N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-Hser(tBu) for Fmoc-Ser(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 255 N-Ac-Sar-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Gln(Trt) for Fmoc-Val. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.36 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1023 (M)⁺.

EXAMPLE 256 N-Ac-Sar-Gly-Nva-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Nvafor Fmoc-Val. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Nva-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)32 3.28 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 994 (M)⁺.

EXAMPLE 257 N-Ac-Sar-Gly-Ile-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Ilefor Fmoc-Val. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Ile-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.55 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M)⁺.

EXAMPLE 258 N-Ac-Sar-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Phefor Fmoc-Val. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.77 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1042 (M)⁺.

EXAMPLE 259 N-Ac-Sar-Gly-Leu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substituting Fmoc-Leufor Fmoc-Val. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Leu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=3.56 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1008 (M)⁺.

EXAMPLE 260 N-Ac-Sar-Gly-Ser-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Ser(tBu) for Fmoc-Val. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Ser-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt: R_(t)=2.41 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 982 (M)⁺.

EXAMPLE 261 N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 was used but substitutingFmoc-Thr(tBu) for Fmoc-Sar and Fmoc-D-Leu for Fmoc-D-Ile. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product was purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions werelyophilized to yield N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt: R_(t)=3.33 min (gradient of 10% to 30%acetonitrile in water containing 0.01% TFA over 30 min period); MS (ESI)m/e 1024 (M)⁺.

EXAMPLE 262

The procedures described in Example 46 is used but substituting theappropriate protected amino acids as describes in Examples 75, 4, 54,and 132. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Ala-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Leu-Ser-Ala-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 263

The procedures described in Example 262 is used but substitutingFmoc-Val for Fmoc-Ala. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Val-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Leu-Ser-Val-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 264

The procedures described in Example 263 is used but substitutingFmoc-DNva for Fmoc-Val. After cleavage of the peptide from the resin andremoval of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Ile-Ser-D-Nva-Ile-Arg-Pro-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Leu-Ser-D-Nva-Ile-Arg-Pro-ProNHCH₂CH₃.

EXAMPLE 265 N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-D-Ile for Fmoc-D-Leu and Fmoc-Gln(Trt) for Fmoc-Nva. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃as the trifluoroacetate salt.

EXAMPLE 266 N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 267 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 75 is used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Ser(tBu) for Fmoc-Thr(tBu). Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 268 N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 267 is used but substitutingFmoc-D-Ile for Fmoc-D-Leu and Fmoc-Ser(tBu) for Fmoc-Thr(tBu). Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-Pro D-AlaNH₂ as thetrifluoroacetate salt.

EXAMPLE 269 N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 54 is used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Ser(tBu) for Fmoc-Thr(tBu). Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt

EXAMPLE 270 N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 269 is used but substitutingFmoc-D-Ile for Fmoc-D-Leu. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 271 N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 270 is used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Gln(Trt) for Fmoc-Nva. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 272 N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 270 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 273 N-Ac-Sar-Gly-Val-D-Ile-Ser-Ser-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 265 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 274 N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 266 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 275 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃

The procedure described in Example 13 is used but substitutingFmoc-D-Leu for Fmoc-D-Ile and Fmoc-Ser(tBu) for Fmoc-Thr(tBu). Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 276 N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃

The procedure described in Example 13 is used but substitutingFmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 277 N-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substituting Fmoc-Leufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 278 N-Ac-Sar-Gly-Val-D-Ile-Ser-Leu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 277 is used but substitutingFmoc-D-Ile for Fmoc-D-Leu. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Ser-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 279 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 132 is used but substitutingFmoc-D-alloIle for Fmoc-D-Leu. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 280 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 265 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 281 N-Succinyl-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 270 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Succinyl-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 282 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃

The procedure described in Example 276 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure factions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃ as thetrifluoroacetate.

EXAMPLE 283 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂

The procedure described in Example 268 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized toN-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂ as thetrifluoroacetate.

EXAMPLE 284 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Leu-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 265 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile and Fmoc-Leu for Fmoc-Gln(Trt). Aftercleavage of the peptide from the resin and removal of the protectinggroups using (9:1) TFA/anisole (3 mL) the crude product is purified byC-18 column chromatography using a solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Leu-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 285 N-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 276 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 286

The procedure described in Example 125 is used but separatelysubstituting Fmoc-D-Ile and Fmoc-D-alloIle, respectively, forFmoc-D-Leu. After cleavage of the peptide from the resin and removal ofthe protecting groups using (9:1) TFA/anisole (3 mL) the crude productis purified by C-I8 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.01%TFA. The pure fractions are lyophilized to the the following peptides astrifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-Ile-Gly-Nva-Ile-Arg-ProNHCH₂CH₃ and

N-Ac-Sar-Gly-Val-D-alloIle-Gly-Nva-Ile-Arg-ProNHCH₂CH₃

EXAMPLE 287

The procedure described in Example 125 and 286 is used but separatelysubstituting Fmoc-D-Ile and Fmoc-D-alloIle, respectively, for Fmoc-D-Leuand substituting Fmoc-Gln(Trt) for Fmoc-Nva . After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the trifluoroacetate salt of:

N-Ac-Sar-Gly-Val-D-Leu-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-alloIle-Gly-Gln-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 288

The procedure described in Example 123 is used but separatelysubstituting Fmoc-D-Ile and Fmoc-D-alloIle, respectively, forFmoc-D-Leu. After cleavage of the peptide from the resin and removal ofthe protecting groups using (9:1) TFA/anisole (3 mL) the crude productis purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.01%TFA. The pure fractions are lyophilized to yield the trifluoroacetatesalt of:

N-Ac-Sar-Gly-Val-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃ andN-Ac-Sar-Gly-Val-D-alloIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 289

The procedure described in Example 123 and 288 is used but separatelysubstituting Fmoc-D-Ile and Fmoc-D-alloIle, respectively, for Fmoc-D-Leuand substituting Fmoc-Gln(Trt) for Fmoc-Nva. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the trifluoroacetate salt of:

N-Ac-Sar-Gly-Val-D-Leu-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-alloIle-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 290 N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Ar-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Ser(tBu) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 291 N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Thr(tBu) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 292 N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Gln(Trt) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 293 N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Asn(Trt) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 294 N-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Arg(Pmc) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 295 N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-3-Pal for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 296 N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Glu(OtBu)-OH for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 297 N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Asp(OtBu)-OH for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 298 N-Ac-Sar-Gly-Val-D-His-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-His(Boc)-OH for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-His-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 299 N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-Hser(tBu) for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 300 N-Ac-Sar-Gly-Val-D-alloThr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-D-alloThr(tBu) for Fmoc-D-Ile. After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloThr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 301 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substituting Fmoc-D-Ilefor Fmoc-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 302 N-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 290 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 303 N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 291 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 304 N-Ac-Sar-Gly-Val-D-alloThr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 300 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloThr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 305 N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 290 is used but substitutingFmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized toN-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 306 N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 291 is used but substitutingFmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 307 N-Ac-Sar-Gly-Val-D-alloThr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 300 is used but substitutingFmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloThr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 308 N-Ac-Sar-Gly-Val-D-alloThr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 304 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-alloThr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 309 N-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 303 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 310

The procedure described in Examples 132 and 266 is used but substitutingN-acetyl-6-aminocaproic acid (6-Ac-Aca) for acetic acid. After cleavageof the peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides as trifluoroacetate salt:

N(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH CH₃, andN-(6Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH2CH₃

EXAMPLE 311

The procedure described in Examples 310 is used but substitutingN-acetyl-4-aminobutyric acid (4-Ac-Gaba) instead ofN-acetyl-6-aminocaproic acid. After cleavage of the peptide from theresin and removal of the protecting groups using (9:1) TFA/anisole (3mL) the crude product is purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure factions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 312

The procedure described in Examples 311 is used but substituting2-furoic acid instead of N-acetyl-4-aminobutyric acid. After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides as trifluoroacetate salt:

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-ArgProNHCH₂CH₃, and

N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 313

The procedure described in Examples 312 is used but substitutingshikimic acid instead of 2-furoic acid. After cleavage of the peptidefrom the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides as trifluoroacetate salt:

EXAMPLE 315

The procedure described in Examples 311 is used but substituting2-methyl-nicotinic acid instead of 2-furoic acid. After cleavage of thepeptide from the resin and removal of the protecting groups using (9:1)TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yield the following peptides as trifluoroacetate salt:

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, and

N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

EXAMPLE 316N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl

The procedure described in Example 8 is used but substituting Fmoc-D-Leufor Fmoc-D-Ile and Fmoc-Ser(tBu) for Fmoc-Thr(tBu). After cleavage ofthe peptide from the resin and removal of the protecting groups using(9:1) TFA/anisole (3 mL) the crude product is purified by C-18 columnchromatography using a solvent mixture varying in a gradient of 10% to50% acetonitrile-water containing 0.01% TFA. The pure fractions arelyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl asthe trifluoroacetate.

EXAMPLE 317N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHethyl-1-(R)cyclohexyl

The procedure described in Example 8 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl asthe trifluoroacetate.

EXAMPLE 318N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl

The procedure described in Example 8 is used but substituting Fmoc-Leufor Fmoc-Nva. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl asthe trifluoroacetate.

EXAMPLE 319N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl

The procedure described in Example 8 is used but substituting Fmoc-D-Leufor Fmoc-D-Ile. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)cyclohexyl as thetrifluoroacetate.

EXAMPLE 320N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl

The procedure described in Example 316 is used but substitutingFmoc-Ser(tBu) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 100% to 50% acetonitrile-watercontaining 0.01% TFA1 The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHethyl-1-(R)cyclohexyl as thetrifluoroacetate.

EXAMPLE 321N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl

The procedure described in Example 316 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups using (9:1) TFA/anisole (3 mL) thecrude product is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl asthe trifluoroacetate.

EXAMPLE 322N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(S)cyclohexyl

The procedure described in Example 8 is used but substituting(S)-1-cycloxylethylamine for (R)-1-cycloxylethylamine. After cleavage ofthe peptide from the resin and removal of the protecting groups thecrude product was purified by C-18 column chromatography using solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(S)-cyclohexyl asthe trifluoroacetate salt.

EXAMPLE 323

The procedures described in Example 98 is used but substituting theappropriate protected amino acids as describes in Examples 132, 43, 54,and 75. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Gly-Nva-Ile-Arg-ProNHCH₂CH₃.

N-Ac-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH(CH₃)₂,

N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sat-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH(CH₃)2.

EXAMPLE 324 N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 98 is used but substitutingFmoc-D-Cys(Trt) for Fmoc-D-Pen(Trt). After cleavage of the peptide fromthe resin and removal of the protecting groups using (9:1) TFA/anisole(3 mL) the crude product is purified by C-18 column chromatography usinga solvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yieldN-N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate.

EXAMPLE 325

The procedures described in Example 324 is used but substituting theappropriate protected amino acids as describes in Examples 132, 43, 54,and 75. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH(CH₃)₂,

N-Succinyl-Sar-Gly-Val-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Gly-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Thr-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 326 N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Pen(Trt) for Fmoc-Val. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 327 N-Ac-Sar-Gly-Cys-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 1 is used but substitutingFmoc-Cys(Trt) for Fmoc-Val. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Cys-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 328

The procedures described in Example 326 is used but substituting theappropriate protected amino acids as describes in Examples 14, 15, 132,43, 54, and 75. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Pen-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂.

EXAMPLE 329 N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 120 is used but substitutingFmoc-Pen(Trt) for Fmoc-Ala. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 330

The procedures described in Example 329 is used but substituting theappropriate protected amino acids as describes in Examples 14, 15, 132,43, 54, and 75. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-alloIle-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Ser-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH(CH₃)2.

EXAMPLE 331 N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₂OCH₃

The procedure described in Example 11 is used but substitutingFmoc-Pen(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using solvent mixture varying in a gradientof 10% to 50% acetonitrile water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₂OCH₃ as thetrifluoroacetate salt.

EXAMPLE 332

The procedures described in Example 331 is used but substituting theappropriate protected amino acids as describes in Examples 14, 15, 132,43, 54, and 75. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Leu-Gly-Pen-Ile-Arg-ProNHCH₂CH₃, and

N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 333N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 96 is used but substitutingFmoc-Gln(Trt) for Fmoc-Nva. After cleavage of the peptide from the resinand removal of the protecting groups the crude product was purified byC-18 column chromatography using solvent mixture varying in a gradientof 10% to 50% acetonitrile-water containing 0.01% TFA. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D)-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 334

The procedures described in Example 333 is used but substituting theappropriate protected amino acids as describes in Examples 132, 43, 54,and 75. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 5% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Gly-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Leu-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, and

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Ser-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 335 N-Ac-Sar-Ala-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in Example 153 is used but substitutingFmoc-D-alloIle for Fmoc-D-Ile. After cleavage of the peptide from theresin and removal of the protecting groups the crude product waspurified by C-18 column chromatography using solvent mixture varying ina gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Ala-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as thetrifluoroacetate salt.

EXAMPLE 336

The procedures described in Example 335 is used but substituting theappropriate protected amino acids as described in Examples 132, 43, 54,and 75. After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-Ac-Sar-Ala-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Ac-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH₂CH₃,

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH(CH₃)₂, and

N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-Pro-D-AlaNH₂.

EXAMPLE 337

The procedure described in Example 231 used but substitutingN-acetyl-beta-alanine (3-Ac-Bala) for N-acetyl-4-aminobutyric acid.After cleavage of the peptide from the resin and removal of theprotecting groups using (9:1) TFA/anisole (3 mL) the crude product ispurified by C-18 column chromatography using a solvent mixture varyingin a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Thepure fractions are lyophilized to yield the following peptides astrifluoroacetate salt:

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,

N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, and

N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃.

EXAMPLE 338 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH

The procedure described in Example 1 is used but substituting omittingthe coupling with ethylamine. After cleavage of the peptide from theresin and removal of the protecting groups the crude product waspurified by C-18 column chromatography using solvent mixture varying ina gradient of 10% to ⁵⁰% acetonitrile-water containing 0.01% TFA. Thepure fractions were lyophilized to yieldN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH as the trifluoroacetatesalt.

EXAMPLE 339

The procedures described in Example 338 is used but substituting theappropriate protected amino acids as described in Examples 14, 15, 132,43, 54, and 75. After cleavage of the peptide from the resin and removalof the protecting groups using (9:1) TFA/anisole (3 mL) the crudeproduct is purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.01% TFA. The pure fractions are lyophilized to yield thefollowing peptides as trifluoroacetate salt:

N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH,

N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-Pro-OH,

N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH, and

N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-Pro-OH.

EXAMPLE 340 N-Ac-Sar-Gly-Asp-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

In an Applied Biosystems 433A peptide synthesizer, 0.1 mM ofFmoc-Pro-Sieber ethylamide resin was placed in the reaction vessel andcartridges of 1 mM amino acids were sequentially loaded. The Fastmoc 0.1with previous peak monitoring protocol was used. The following is thesynthetic cycle:

1. Solvating resin with N-methylpyrrolidone (NMP) for about 5 minutes;

2. Washing with NMP for about 5 minutes;

3. Removing the Fmoc group using 50% piperidine solution in NMP for 5minutes, washing and repeating the process 3 to 4 times;

4. Activating the Fmoc-amino acid using 1 mM of 0.5 M solution of2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) in DMF;

5. Adding the activated Fmoc-amino acid to the reaction vessel followedby 1 mM of 2 M diisopropylamine in NMP solution;

6. Coupling of the Fmoc-amino acid for 20 minutes;

7. Washing and removal of Fmoc-group using 50% piperidine in NMP.

The following protected amino acids were sequentially coupled to theresin using above protocol in Table 2, below:

TABLE 2 Amino acid Coupling time 1. Fmoc-Arg(Pmc) 20 minutes 2. Fmoc-Ile20 minutes 3. Fmoc-Nva 20 minutes 4. Fmoc-Thr(t-Bu) 20 minutes 5.Fmoc-D-Leu 20 minutes 6. Fmoc-Asp(OtBu) 20 minutes 7. Fmoc-Gly 20minutes 8. Fmoc-Sar 20 minutes 9. acetic acid 20 minutes

Upon completion of the synthesis the resin-bound peptide was washed withmethanol three times and dried in vacuo, then treated with a (95:5)TFA/water solution (3mL) at room temperature overnight. The resin wasfiltered and washed 3 times with methanol. The filtrates and the washeswere combined and concentrated in vacuo. The residue was treated withether and the precipitate was filtered to give the crude peptide asamorphous powder. This was purified by preparative HPLC using C-18column with a mixture of solvents varying in a gradient from 5% to 100%acetonitrile/water containing 0.1% TFA over a period of 50 min. The purefractions were lyophilized to yieldN-Ac-Sar-Gly-As-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=2.23 min (using C-18 column and solvents mixture varying ina gradient from 20% to 95% acetonitrile/water containing 10 mM ammoniumacetate over a period of 10 min); MS (ESI) m/e 1010 (M⁺).

EXAMPLE 341 N-Ac-Sar-Gly-Ala-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Ala for Fmoc-Asp(OtBu). After cleavage of the peptide from theresin and removal of the protecting groups the product was precipitatedwith ether. The crude compound was purified by preparative HPLC to giveN-Ac-Sar-Gly-Ala-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=2.828 min (using C-18 column and solvents mixture varying ina gradient from 20% to 95% acetonitrile/water containing 10 mM ammoniumacetate over a period of 10 min); MS (ESI) m/e 966 (M⁺).

EXAMPLE 342 N-Ac-Sar-Gly-Cha-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Cha for Fmoc-Asp(OtBu). After cleavage of the peptide from theresin and removal of the protecting groups the product was precipitatedwith ether. The crude compound was purified by preparative HPLC to giveN-Ac-Sar-Gly-Cha-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=4.48 min (using C-18 column and solvents mixture varying ina gradient from 20% to 95% acetonitrile/water containing 10 mM ammoniumacetate over a period of 10 min); MS (ESI) m/e 1048 (M⁺).

EXAMPLE 343 N-Ac-Sar-Gly-Met-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Met for Fmoc-Asp(OtBu) and Fmoc-D-Ile for Fmoc-D-Leu. Aftercleavage of the peptide from the resin and removal of the protectinggroups the product was precipitated with ether. The crude compound waspurified by preparative HPLC to giveN-Ac-Sar-Gly-Met-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=3.25 min (using C-18 column and solvents mixture varying ina gradient from 20% to 95% acetonitrile/water containing 10 mM ammoniumacetate over a period of 10 min); MS (ESI) m/e 1026 (M+H); Amino AcidAnal.: 1.09 Sar; 0.97 Gly; 0.94 Met; 2.08 Ile; 0.47 Thr; 1.00 Nva; 1.34Arg; 1.01 Pro.

EXAMPLE 344 N-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Cit for Fmoc-Sar, Fmoc-Val for Fmoc-Asp(OtBu) and Fmoc-D-Ile forFmoc-D-Leu. After cleavage of the peptide from the resin and removal ofthe protecting groups the product was precipitated with ether. The crudecompound was purified by preparative HPLC toN-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=2.97 min (using C-18 column and solvents mixture varying ina gradient from 20% to 95% acetonitrile/water containing 10 mM ammoniumacetate over a period of 10 min); MS (ESI) m/e 1080 (M+H); Amino AcidAnal.: 0.98 Cit; 0.93 Gly; 0.98 Val; 2.05 Ile; 0.51 Thr; 0.99 Nva; 1.37Arg; 1.01 Pro.

EXAMPLE 345 N-Ac-Sar-Gly-Val-D-Ile-Thr-Hser-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Hser(t-Bu) for Fmoc-Nva, Fmoc-Val for Fmoc-Asp(OtBu), andFmoc-D-Ile for Fmoc-D-Leu. After cleavage of the peptide from the resinand removal of the protecting groups the product was precipitated withether. The crude compound was purified by preparative HPLC to giveN-Ac-Sar-Gly-Val-D-Ile-Thr-Hser-Ile-Arg-ProNHCH₂CH₃ as trifluoroacetatesalt; R_(t)=2.782 min (using C-18 column and solvents mixture varying ina gradient from 10% to 40% acetonitrile/water containing 0.1% TFA over aperiod of 33 min); MS (ESI) m/e 996 (M+H); Amino Acid Anal.: 1.00 Sar;0.95 Gly; 1.01 Val; 1.99 Ile; 0.60 Thr; 1.07 Arg; 1.04 Pro.

EXAMPLE 346 N-Ac-Sar-Gly-Val-D-alloIle-His-Nva-Ile-Arg-ProNHCH₂CH₃

The procedure described in example 340 was used but substitutingFmoc-Val for Fmoc-Asp(OtBu), Fmoc-D-alloIle for Fmoc-D-Leu, andFmoc-His(Boc) for Fmoc-Thr(t-Bu). After cleavage of the peptide from theresin and removal of the protecting groups the product was precipitatedwith ether. The crude compound was purified by preparative HPLC to giveN-Ac-Sar-Gly-Val-D-alloIle-His-Nva-Ile-Arg-ProNHCH₂CH₃ as atrifluoroacetate salt; R_(t)=3.12 min (using C-18 column and solventsmixture varying in a gradient from 10% to 40% acetonitrile/watercontaining 0.1% TFA over a period of 33 min); MS (ESI) m/e 1030 (M⁺).

EXAMPLE 347 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-Butyl ResinPreparation

4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin (0.5 g, 0.54 mmol/gsubstitution) was placed in a solid phase synthesis reaction vesselcontaining (9:1) DMA/acetic acid (4 mL). The mixture was shaken for 5min. The resin was drained and this process was repeated three times. Tothe swollen resin were added 10-15 grains of activated 4A molecularsieves and (9:1) DMA/acetic acid (4mL) and 10 molar equivalents ofn-butylamine. The slurry was shaken for 1 h at rt and to it was added 10molar equivalents of sodium triacetoxyborohydride. The slurry was shakenfor 2 h at rt. The resin was drained and washed three times with DMA,three times with methanol, three times with dichloromethane, three timeswith diethyl ether and dried in vacuo at rt overnight. The dry resin wasswollen in DMA (4 mL) and shaken for 5 min. This process was repeatedtwice.

Coupling of Fmoc-Pro

To the swollen resin in the reaction vessel were added sequentially thefollowing chemicals: DMA (4 mL), one equivalent of DIEA, a DMA solutioncontaining 3.0 equivalents of Fmoc-Pro, 3.0 equivalents of HATU, and 3.0equivalents of DIEA. The slurry was shaken overnight. The resin wasdrained and washed three times with DMA, three times with methanol,three times with dichloromethane, three times with diethyl ether anddried in vacuo at rt overnight. A small portion of the resin was used todetermine the Fmoc-Pro loading. The rest of the resin was shaken withDMA (4 mL) three times for 5 min and then for 1 h at rt with a solutionof (8:1:1) DMA/pyridine/acetic anhydride (5 mL). The resin was drainedand washed three times with DMA, three times with methanol, three timeswith dichloromethane, and three times with diethyl ether. The resin wasdried in vacuo at rt overnight and then used in the subsequent solidphase peptide synthesis.

Synthesis of Peptide

In the synthesis of the above peptide, the amino acids, the couplingconditions and the synthetic protocol used were identical to thosedescribed in Example 340. Upon completion of the synthesis the peptideand the protecting groups were cleaved at rt using (95:5) TFA/water (3mL) for 3h. The resin was filtered and washed three times with methanol.The combined filtrates were concentrated in vacuo and to the residue wasadded diethylether. The solid precipitate was filtered. The crudeproduct was purified by C-18 column chromatography using a solventmixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized to yieldNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-Butyl as thetrifluoroacetate salt: R_(t)=3.792 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1022 (M⁺).

EXAMPLE 348 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Butyl

The procedure described in example 347 was used but substitutingisobutylamine for n-butylamine. After cleavage of the peptide from theresin and precipitation with ether the crude product was obtained. Thiswas purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.1%TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Butyl as thetrifluoroacetate salt: R_(t)=3.731 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1022 (M⁺).

EXAMPLE 349 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Amyl

The procedure described in example 347 was used but substitutingisoamylamine for n-butylamine. After cleavage of the peptide from theresin and precipitation with ether the crude product was obtained. Thiswas purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.1%TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Amyl as thetrifluoroacetate salt: R_(t)=4.086 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1036 (M⁺).

EXAMPLE 350 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-hexyl

The procedure described in example 347 was used but substituting inn-hexylamine for n-butylamine. After cleavage of the peptide from theresin and precipitation with ether the crude product was obtained. Thiswas purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.1%TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-Ile-Thr-Nva-Ile-Arg-ProNH-n-Hexyl as the trifluoroacetatesalt: R_(t)=4.527 min (gradient of 20% to 95% acetonitrile in watercontaining 0.01 M NH₄Ac over 10 min period); MS (ESI) m/e 1050 (M³⁰ ).

EXAMPLE 351N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(3,3-dimethyl)butyl

The procedure described in example 347 was used but substituting(3,3-dimethyl)butylamine for n-butylamine. After cleavage of the peptidefrom the resin and precipitation with ether the crude product wasobtained. This was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3,3-dimethyl)butyl as thetrifluoroacetate salt: R_(t)=4.366 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1050 (M⁺).

EXAMPLE 352 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-ethoxy)ethyl

The procedure described in example 347 was used but substituting(2-ethoxy)ethylamine for n-butylamine. After cleavage of the peptidefrom the resin and precipitation with ether the crude product wasobtained. This was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-ethoxy)ethyl as thetrifluoroacetate salt: R_(t)=3.356 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1038 (M⁺).

EXAMPLE 353N-Ac-Sar-Gly-Val-D-Ile-T-Nva-Ile-Arg-ProNH-(2-isopropoxy)ethyl

The procedure described in example 347 was used but substituting(2-isopropoxy)ethylamine for n-butylamine. After cleavage of the peptidefrom the resin and precipitation with ether the crude product wasobtained. This was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-isopropoxy)ethyl as thetrifluoroacetate salt: R_(t)=3.57 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1052 (M⁺).

EXAMPLE 354N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3-methoxy)propyl

The procedure described in example 347 was used but substituting(3-methoxy)propylamine for n-butylamine. After cleavage of the peptidefrom the resin and precipitation with ether the crude product wasobtained. This was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3-methoxy)propyl as thetrifluoroacetate salt: R_(t)=3.26 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1038 (M⁺).

EXAMPLE 355N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(cyclopentyl)methyl

The procedure described in example 347 was used but substituting(cyclopentyl)methylamine for n-butylamine. After cleavage of the peptidefrom the resin and precipitation with ether the crude product wasobtained. This was purified by C-18 column chromatography using asolvent mixture varying in a gradient of 10% to 50% acetonitrile-watercontaining 0.1% TFA. The pure fractions were lyophilized toNAc-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(cyclopentyl)methyl as thetrifluoroacetate salt-R_(t)=4.148 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1048 (M⁺).

EXAMPLE 356 N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-cyclohexyl

The procedure described in example 347 was used but substitutingcyclohexylamine for n-butylamine. After cleavage of the peptide from theresin and precipitation with ether the crude product was obtained. Thiswas purified by C-18 column chromatography using a solvent mixturevarying in a gradient of 10% to 50% acetonitrile-water containing 0.1%TFA. The pure fractions were lyophilized toNAcSar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg- ProNH-cyclohexyl as thetrifluoroacetate salt: R_(t)=4.070 min (gradient of 20% to 95%acetonitrile in water containing 0.01 M NH₄Ac over 10 min period); MS(ESI) m/e 1048 (M⁺).

In Vitro Assay for Angiogenic Activity

The human microvascular endothelial (HMVEC) migration assay was runaccording to the procedure of S. S. Tolsma, O. V. Volpert, D. J. Good,W. F. Frazier, P. J. Polverini and N. Bouck, J. Cell Biol. 122, 497-511(1993).

The HMVEC migration assay was carried out using Human MicrovascularEndothelial Cells-Dermal (single donor) and Human MicrovascularEndothelial Cells, (neonatal). The BCE or HMVEC cells were starvedovernight in DME containing 0.1% bovine serum albumin (BSA). Cells werethen harvested with trypsin and resuspended in DME with 0.1% BSA at aconcentration of 1.5×10⁶ cells per ml. Cells were added to the bottom ofa 48 well modified Boyden chamber (Nucleopore Corporation, Cabin John,MD). The chamber was assembled and inverted, and cells were allowed toattach for 2 hours at 37° C. to polycarbonate chemotaxis membranes (5 μmpore size) that had been soaked in 0.1% gelatin overnight and dried. Thechamber was then reinverted, and test substances (total volume of 50μl), including activators, 15 ng/ml bFGF/VEGF, were added to the wellsof the upper chamber. The apparatus was incubated for 4 hours at 37° C.Membranes were recovered, fixed and stained (Diff Quick, FisherScientific) and the number of cells that had migrated to the upperchamber per 3 high power fields counted. Background migration to DME+0.1 BSA was subtracted and the data reported as the number of cellsmigrated per 10 high power fields (400X) or, when results from multipleexperiments were combined, as the percent inhibition of migrationcompared to a positive control.

The compounds described in Examples 1 to 339 inhibited human endothelialcell migration in the above assay from about 30% to about 95% inhibitionwhen tested at concentrations of 10 nM or 20 nM, as reported below inTable 3.

TABLE 3 In Vitro Angiogenic Activity % Inhib. % Inhib. Ex. # @ 20 nM @10 nM 1 87.3 76.9 3 56.0 — 4 71.3 — 5 — 87.2 8 — 88.2 11 70.4 — 12 55.8— 18 — 51.4 28 — 47.0 42 60.2 — 43 — 94.1 46 77.5 — 47 69.7 — 49 83.4 —50 71.6 — 51 67.0 — 52 46.5 — 53 76.7 — 54 81.3 — 55 59.2 — 56 49.9 — 5756.6 — 58 68.8 — 59 82.3 — 60 75.3 — 61 — 83.7 63 — 82.4 66 76.1 —

6 1 10 PRT Artificial Sequence Antiangiogenetic Peptide 1 Xaa Xaa XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 2 9 PRT Artificial SequenceAntiangiogenetic peptide 2 Xaa Gly Val Ile Thr Xaa Ile Arg Pro 1 5 3 9PRT Artificial Sequence Antiangiogenetic peptide 3 Xaa Gly Val Gly ThrXaa Ile Arg Pro 1 5 4 9 PRT Artificial Sequence Antiangiogenetic peptide4 Xaa Gly Val Xaa Thr Xaa Ile Arg Pro 1 5 5 9 PRT Artificial SequenceAntiangiogenetic peptide 5 Xaa Gly Val Xaa Thr Xaa Ile Arg Pro 1 5 6 11PRT Artificial Sequence Antiangiogenetic Peptide 6 Xaa Xaa Gly Val XaaXaa Xaa Ile Arg Pro Xaa 1 5 10

What is claimed is:
 1. A compound of the formula:A₀-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀ or a pharmaceutically acceptable salt,ester, solvate or prodrug thereof, wherein: A₀ is an acyl group selectedfrom: (1) R—(CH₂)_(n)—C(O)—; wherein n is an integer from 0 to 8 and Ris selected from hydroxyl; methyl; N-acetylamino; methoxyl; carboxyl;cyclohexyl optionally containing one or two double bonds and optionallysubstituted with one to three hydroxyl groups; and a 5- or 6-memberedaromatic or nonaromatic ring optionally containing one or twoheteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ringis optionally substituted with a moiety selected from alkyl, alkoxy, andhalogen; and (2) R¹—CH₂CH₂—OCH₂CH₂O)_(p)—CH₂—C(O)—; wherein R¹ isselected from hydrogen, alkyl, and N-acetylamino, and p is an integerfrom 1 to 8; A₁ is an amino acyl residue selected from: (1) alanyl, (2)asparaginyl, (3) citrullyl, (4) glutaminyl, (5) glutamyl, (6)N-ethylglycyl, (7) methionyl, (8) N-methylalanyl, (9) prolyl, (10)pyro-glutamyl, (11) sarcosyl, (12) seryl, (13) threonyl, (14)—HN—(CH₂)_(q)—C(O)—, wherein q is 1 to 8, and (15)—HN—CH₂CH₂—(OCH₂CH₂O)_(r)—CH₂—C(O)—, wherein r is 1 to 8; A₂ is an aminoacyl residue selected from: (1) alanyl, (2) asparaginyl, (3) aspartyl,(4) glutaminyl, (5) glutamyl, (6) leucyl, (7) methionyl, (8)phenylalanyl, (9) prolyl, (10) seryl, (11) —HN—(CH₂)_(q)—C(O)—, whereinq is 1 to 8, (12) —HN—CH₂CH₂—(OCH₂CH₂O)_(r)—CH₂—C(O)—, wherein r is 1 to8 and (13) glycyl; A₃ is an amino acyl residue selected from: (1)alanyl, (2) asparaginyl, (3) citrullyl, (4) cyclohexylalanyl, (5)cyclohexylglycyl, (6) glutaminyl, (7) glutamyl, (8) glycyl, (9)isoleucyl, (10) leucyl, (11) methionyl, (12) norvalyl, (13)phenylalanyl, (14) seryl, (15) t-butylglycyl, (16) threonyl, (17) valyl,(18) penicillaminyl, and (19) cystyl; A₄ is an amino acyl residueselected from: (1) L- or D-allo-isoleucyl, (2) glycyl, (3) L- orD-isoleucyl, (4) L- or D-prolyl, (5) L- or D-dehydroleucyl, (6)D-alanyl, (7) D-3-(naphth-1-yl)alanyl, (8) D-3-(naphth-2-yl)alanyl, (9)D-(3-pyridyl)-alanyl, (10) D-2-aminobutyryl, (11) D-allo-threonyl, (12)D-allylglycyl, (13) D-asparaginyl, (14) D-aspartyl, (15)D-3-(3-benzothienyl)alanyl (16) D-3-(4,4′-biphenyl)alanyl, (17)D-3-(3-chlorophenyl)alanyl, (18) D-3-(4-chlorophenyl)alanyl, (19)D-3-(3-trifluoromethylphenyl)alanyl, (20) D-3-(3-cyanophenyl)alanyl,(21) D-3-(3,4-difluorophenyl)alanyl, (22) D-citrullyl, (23)D-cyclohexylalanyl, (24) D-cyclohexylglycyl, (25) D-cystyl, (26)D-cystyl(S-t-butyl), (27) D-glutaminyl, (28) D-glutamyl, (29)D-histidyl, (30) D-homoisoleucyl, (31) D-homophenylalanyl, (32)D-homoseryl, (33) D-leucyl, (34) D-lysyl(N-epsilon-nicotinyl), (35)D-lysyl, (36) D-methionyl, (37) D-neopentylglycyl, (38) D-norleucyl,(39) D-norvalyl, (40) D-ornithyl, (41) D-penicillaminyl, (42)D-penicillaminyl(acetamidomethyl), (43) D-penicillaminyl(S-benzyl), (44)D-phenylalanyl, (45) D-3-(4-aminophenyl)alanyl, (46)D-3-(4-methylphenyl)alanyl, (47) D-3-(4-nitrophenyl)alanyl, (48)D-3-(3,4dimethoxyphenyl)alanyl, (49) D-3-(3,4,5-trifluorophenyl)alanyl,(50) D-seryl, (51) D-seryl(O-benzyl), (52) D-t-butylglycyl, (53)D-thienylalanyl, (54) D-threonyl, (55) D-threonyl(O-benzyl), (56)D-tryptyl, (57) D-tyrosyl(O-benzyl), (58) D-tyrosyl(O-ethyl), (59)D-tyrosyl, and (60) D-valyl; A₅ is a glycyl residue or an amino acylresidue of L or D configuration selected from: (1) alanyl, (2)(3-pyridyl)alanyl, (3) 3-(naphth-1-yl)alanyl, (4) 3-(naphth-2-yl)alanyl,(5) allo-threonyl, (6) allylglycyl, (7) glutaminyl, (8) histidyl, (9)homoseryl, (10) isoleucyl, (11) lysyl(N-epsilon-acetyl), (12) methionyl,(13) norvalyl, (14) octylglycyl, (15) ornmithyl, (16)3-(4-hydroxymethylphenyl)alanyl, (17) prolyl, (18) seryl, (19) threonyl(20) tryptyl, (21) tyrosyl, (22) D-allo-threonyl, (23) D-homoseryl, (24)D-seryl, (25) D-threonyl (26) penicillaminyl, and (27) cystyl; A₆ is aglycyl residue or an amino acyl residue of L or D configuration selectedfrom: (1) alanyl, (2) 3-(naphth-1-yl)alanyl, (3) 3-(naphth-2-yl)alanyl,(4) 3-pyridyl)alanyl, (5) 2-aminobutyryl, (6) allylglycyl, (7) arginyl,(8) asparaginyl, (9) aspartyl, (10) citrullyl, (11)3-(cyclohexyl)alanyl, (12) glutaminyl (13) glutamyl, (14) histidyl, (15)homoalanyl, (16) homoleucyl, (17) homoseryl, (18) isoleucyl, (19)leucyl, (20) lysyl(N-epsilon-acetyl), (21) lysyl(N-epsilon-isopropyl),(22) methionyl(sulfone), (23) methionyl(sulfoxide), (24) methionyl, (25)norleucyl, (26) norvalyl, (27) octylglycyl, (28) phenylalanyl, (29)3-(4-carboxyamidephenyl)alanyl, (30) propargylglycyl, (31) seryl, (32)threonyl, (33) tryptyl, (34) tyrosyl, (35) valyl, (36)D-3-(naphth-1-yl)alanyl, (37) D-3-(naphth-2-yl)alanyl, (38)D-glutaminyl, (39) D-homoseryl, (40) D-leucyl, (41) D-norvalyl, (42)D-seryl), (43) penicillaminyl, and (44) cystyl; A₇ is a glycyl residueor an amino acyl residue of L or D configuration selected from: (1)alanyl, (2) allylglycyl, (3) aspartyl, (4) citrullyl, (5)cyclohexylglycyl, (6) glutamyl, (9) homoseryl, (10) isoleucyl, (11)allo-isoleucyl, (12) leucyl, (13) lysyl(N-epsilon-acetyl), (14)methionyl, (15) 3-(naphth-1-yl)alanyl, (16) 3-(naphth-2-yl)alanyl, (17)norvalyl, (18) phenylalanyl, (19) prolyl, (20) seryl (21) t-butylglycyl,(22) tryptyl, (23) tyrosyl, (24) valyl, (25) D-allo-isoleucyl, (26)D-isoleucyl, (27) penicillaminyl, and (28) cystyl; A₈ is an amino acylresidue selected from: (1) 2-amino-4-[(2-amino)pyrimidinyl]butanoyl, (2)alanyl(3-guanidino), (3) alanyl(3-pyrrolidinylamidino), (4)alanyl[4-piperidinyl(N-amidino)], (5) arginyl, (6)arginyl(N^(G)N^(G′)diethyl), (7) citrully, (8)3-(cyclohexyl)alanyl(4-N′-isopropyl), (8)glycyl[4-piperidinyl(N-amidino)], (10) histidyl, (11) homoarginyl, (12)lysyl, (13) lysyl(N-epsilon-isopropyl), (14) lysyl(N-epsilon-nicotinyl),(15) norarginyl, (16) ornithyl(N-delta-isopropyl), (17)ornithyl(N-delta-nicotinyl), (18) ornithyl[N-delta-(2-imidazolinyl)],(19) [(4-amino(N-isopropyl)methyl)phenyl]alanyl, (20)3-(4-guanidinophenyl)alanyl, and (21)3-(4-amino-N-isopropylphenyl)alanyl; A₉ is an amino acyl residue of L orD configuration selected from: (1) 2-amino-butyryl, (2)2-amino-isobutyryl, (3) homoprolyl, (4) 4-hydroxyprolyl, (5) isoleucyl,(6) leucyl, (7) phenylalanyl, (8) prolyl, (9) seryl, (10) t-butylglycyl,(11) 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, (12) threonyl, (13)valyl, (14) D-alanyl, and (15) D-prolyl; and A₁₀ is selected from: (1)hydroxyl, (2) azaglycylamide, (3) D-alanylamide, (4) D-alanylethylamide,(5) glycylamide, (6) glycylethylamide, (7) sarcosylamide, (8)serylamide, (9) D-serylamide, (10) a group represented by the formula

 and (11) a group represented by the formula —NH—R⁴;  wherein: s is aninteger selected from 0 to 8, R² is selected from hydrogen, alkyl, and a5- to 6-membered cycloalkyl ring; R³ is selected from hydrogen, hydroxy,alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containingfrom one to two heteroatoms selected from oxygen, nitrogen, and sulfur,provided that s is not zero when R³ is hydroxy or alkoxy; and R⁴ isselected from hydrogen, hydroxy, and a 5- to 6-membered cycloalkyl ring.2. A compound according to claim 1, wherein A₁ is sarcosyl, A₂ isglycyl, A₃ is valyl, A₇ is isoleucyl, A₈ is arginyl, A₉ is prolyl, andA₀, A₄, A₅, A₆, and A₁₀ are as defined in claim
 1. 3. A compoundaccording to claim 2, wherein A₄ is an amino acyl residue having a Dconfiguration selected from: (1) D-alanyl, (2) D-3-(naphth-1-yl)alanyl,(3) D-3-(naphth-2-yl)alanyl, (4) D-(3-pyridyl)-alanyl, (5)D-2-aminobutyryl, (6) D-allo-isoleucyl, (7) D-allo-threonyl, (8)D-allylglycyl, (9) D-asparaginyl, (10) D-aspartyl, (11)D-chlorophenylalanyl, (12) D-3-(3-trifluoromethylphenyl)alanyl, (13)D-3-(3-cyanophenyl)alanyl, (14) D-3-(3,4-difluorophenyl)alanyl, (15)D-cyclohexylalanyl, (16) D-cyclohexylglycyl, (17) D-cystyl, (18)D-glutaminyl, (19) D-glutamyl, (20) D-histidyl, (21) D-homoisoleucyl,(22) D-homophenylalanyl, (23) D-homoseryl, (24) D-isoleucyl, (25)D-leucyl, (26) D-lysyl(N-epsilon-nicotinyl), (27) D-methionyl, (28)D-neopentylglycyl, (29) D-norleucyl, (30) D-norvalyl, (31)D-penicillaminyl, (32) D-penicillaminyl(acetamidomethyl), (33)D-penicillaminyl(S-benzyl), (34) D-phenylalanyl, (35)D-3-(4-aminophenyl)alanyl, (36) D-3-(4-methylphenyl)alanyl, (37)D-3-(4-nitrophenyl)alanyl, (38) D-3-(3,4-dimethoxyphenyl)alanyl, (39)D-3-(3,4,5-trifluorophenyl)alanyl, (40) D-prolyl, (41) D-seryl, (42)D-seryl(O-benzyl), (43) D-t-butylglycyl, (44) D-thienylalanyl, (45)D-threonyl, (46) D-threonyl(O-benzyl), (47) D-tyrosyl(O-ethyl), (48)D-tyrosyl, and (49) D-valyl.
 4. A compound according to claim 3, whereinA₄ is an amino acyl residue having a D configuration selected from: (1)D-allo-isoleucyl, (2) D-allylglycyl, (3) D-3-(3-cyanophenyl)alanyl, (4)D-cystyl, (5) D-isoleucyl, (6) D-leucyl, (7) D-penicillaminyl, (8)D-phenylalanyl, (9) D-3-(3,4,5-trifluorophenyl)alanyl, and (10)D-3-(4-aminophenyl)alanyl.
 5. A compound according to claim 2, whereinA₅ is selected from: (1) glycyl, (2) octylglycyl, (3) penicillaminyl,(4) seryl, (5) threonyl, and (6) tyrosyl.
 6. A compound according toclaim 2, wherein A₆ is selected from: (1) glutaminyl, (2) leucyl, (3)norvalyl, and (4) seryl.
 7. A compound according to claim 3 wherein A₀is selected from: (1) acetyl, (2) butyryl, (3) caproyl, (4)(4-N-acetylamino)butyryl, (5) N-acetyl-beta-alanyl, (6)(6-N-acetylamino)caproyl, (7) chloronicotinyl, (8) cyclohexylacetyl, (9)furoyl, (10) 2-methoxyacetyl, (11) methylnicotinyl, (12) nicotinyl, (13)(8-N-acetylamino)-3,6-dioxo-octanoyl, (14) phenylacetyl, (15) propionyl,(16) shikimyl, (17) succinyl, and (18) tetrahydrofuroyl.
 8. A compoundaccording to claim 3, wherein A₁₀ is selected from: (1) D-alanylamide,(2) azaglycylamide, (3) serylamide, (4) ethylamide, (5) hydroxylamide,(6) isopropylamide, (7) propylamide, (8) 2-(cyclohexyl)ethylamide, (9)2-(1-pyrrolidine)ethylamide, (10) 1-(cyclohexyl)ethylamide, (11)2-(methoxy)ethylamide, (12) 2-(hydroxy)ethylamide, (13)2-(2-pyridine)ethylamide, (14) (2-pyridine)methylamide, (15)2-(3-pyridine)ethylamide, (16) 2-(2-(1-methyl)pyrrolidine)ethylamide,(17) 2-(N-morpholine)ethylamide, and (18) cyclopropylmethylamide.
 9. Acompound according to claim 1, wherein A₄ is an amino acyl residuehaving a D configuration selected from: (1) D-allo-isoleucyl, (2)D-allylglycyl, (3) D-3-(3-cyanophenyl)alanyl, (4) D-cystyl, (5)D-isoleucyl, (6) D-leucyl, (7) D-penicillaminyl, (8) D-phenylalanyl, (9)D-3-(3,4,5-trifluorophenyl)alanyl, and (10) D-3-(4-aminophenyl)alanyl;A₅ is an amino acyl residue selected from: (1) octylglycyl, (2) glycyl,(3) penicillaminyl, (4) seryl, (5) threonyl, and (6) tyrosyl; and A₆ isan amino acyl residue selected from: (1) glutaminyl, (2) leucyl, (3)norvalyl, and (4) seryl.
 10. A compound according to claim 9 wherein A₀is selected from: (1) acetyl, (2) butyryl, (3) caproyl, (4)(4-N-acetylamino)butyryl, (5) N-acetyl-beta-alanyl, (6)(6-N-acetylamino)caproyl, (7) chloronicotinyl, (8) cyclohexylacetyl, (9)furoyl, (10) 2-methoxyacetyl, (11) methylnicotinyl, (12) nicotinyl, (13)(8-N-acetylamino)-3,6-dioxo-octanoyl, (14) phenylacetyl, (15) propionyl,(16) shikimyl, (17) succinyl, and (18) tetrahydrofuroyl.
 11. A compoundaccording to claim 9, wherein A₁₀ is selected from: (1) D-alanylamide,(2) azaglycylamide, (3) serylamide, (4) ethylamide, (5) hydroxylamide,(6) isopropylamide, (7) propylamide, (8) 2-(cyclohexyl)ethylamide, (9)2-(1-pyrrolidine)ethylamide, (10) 1-(cyclohexyl)ethylamide, (11)2-(methoxy)ethylamide, (12) 2-(hydroxy)ethylamide, (13)2-(2-pyridine)ethylamide, (14) (2-pyridine)methylamide, (15)2-(3-pyridine)ethylamide, (16) 2-(2-(1-methyl)pyrrolidine)ethylamide,(17) 2-(N-morpholine)ethylamide, and (18) cyclopropylmethylamide.
 12. Acompound, or a pharmaceutically acceptable salt, ester, solvate orprodrug thereof, selected from (1)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (2) (3)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₃, (4)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂, (5)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂-(1-pyrrolidine), (6)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl(1-piperidine), (7)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHmethylcyclopropyl, (8)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(ethyl-1-(R)-cyclohexyl),(9) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂, (10)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, (11)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂cyclohexyl, (12)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂CH₃, (13)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (14)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (15)N-Ac-Sar-Gly-Val-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (16)N-Ac-Sar-Gly-Val-Gly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (17)N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (18)N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (19)N-Ac-Sar-Gly-Val-D-Met-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (20)N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (21)N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (22)N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (23)N-Ac-Sar-Gly-Val-D-4,4′-Biphenylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (24)N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (25)N-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (26)N-Ac-Sar-Gly-Val-D-4-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (27)N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (28)N-Ac-Sar-Gly-Val-Dehydroleu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (29)N-Ac-Sar-Gly-Val-D-3-CF₃Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (30)N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (31)N-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (32)N-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (33)N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (34)N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (35)N-Ac-Sar-Gly-Val-D-Ile-Thr-DNva-Ile-Arg-ProNHCH₂CH₃, (36)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (37)N-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃, (38)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gly-Ile-Arg-ProNHCH₂CH₃, (39)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH₂CH₃, (40)N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH₂CH₃, (41)N-Ac-Sar-Gly-Val-D-Ile-Thr-Abu-Ile-Arg-ProNHCH₂CH₃, (42)N-Ac-Sar-Gly-Val-D-Ile-Thr-Allylgly-Ile-Arg-ProNHCH₂CH₃, (43)N-Ac-Sar-Gly-Val-D-Ile-Thr-Octylgly-Ile-Arg-ProNHCH₂CH₃, (44)N-Ac-Sar-Gly-Val-D-Ile-Thr-Met-Ile-Arg-ProNHCH₂CH₃, (45)N-Cyclohexylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (46)N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (47)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (48)N-Nicotinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (49)N-Propionyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (50)N-(MeO)acetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (51)N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (52)N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (53)N-Butyryl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (54)N-[2-THFcarbonyl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (55)N-[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(56)N-[6-N-acetyl-(CH₂)₅C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(57) N-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (58)N-[4-N-Acetylaminobutyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(59) (60) N-Ac-Sar-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (61)N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(62) N-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (63)N-Ac-Gly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (64)N-Ac-Ala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (65)N-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (66)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (67)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃, (68)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂, (69)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH₂CH₃, (70)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-AbuNHCH₂CH₃, (71)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Phe-NHCH₂CH₃, (72)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Tic-NHCH₂CH₃, (73)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Hyp-NHCH₂CH₃, (74)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Aib-NHCH₂CH₃, (75)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-D-Ala-NHCH₂CH₃, (76)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pip-NHCH₂CH₃, (77)N-Ac-Sar-Gly-Val-D-Tyr(Et)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (78)N-Ac-Sar-Gly-Val-D-Cys(tBu)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (79)N-Ac-Sar-Gly-Val-D-Cys(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (80)N-Ac-Sar-Gly-Val-D-Tyr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (81)N-Ac-Sar-Gly-Val-D-Ser(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (82)N-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (83)N-Ac-Sar-Gly-Val-D-tButylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (84)N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (85)N-Ac-Sar-Gly-Val-D-Thr(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (86)N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (87)N-Ac-Sar-Gly-Val-D-Phe(4-Me)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (88)N-Ac-Sar-Gly-Val-D-Phe(3,4diMeO)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (89)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (90)N-Ac-Sar-Gly-Val-D-Phe(4-NO₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (91)N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (92)N-Ac-Sar-Gly-Val-D-Pen(Acm)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (93)N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (94)N-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (95)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH₂CH₃, (96)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH₂CH₃, (97)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH₂CH₃, (98)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProNHCH₂CH₃, (99)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-ProNHCH₂CH₃, (100)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-ProNHCH₂CH₃, (101)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-ProNHCH₂CH₃, (102)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃, (103)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃, (104)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-ProNHCH₂CH₃, (105)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃, (106)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃, (107)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-ProNHCH₂CH₃, (108)N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃, (109)N-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-Ile-Arg-ProNHCH₂CH₃, (110)N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃, (111)N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃, (112)N-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-Ile-Arg-ProNHCH₂CH₃, (113)N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (114)N-Ac-Sar-Gly-Val-D-Leu-Lys(Ac)-Nva-Ile-Arg-ProNHCH₂CH₃, (115)N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃, (116)N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃, (117)N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃, (118)N-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-Ile-Arg-ProNHCH₂CH₃, (119)N-Ac-Sar-Gly-Val-D-Leu-Met-Nva-Ile-Arg-ProNHCH₂CH₃, (120)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (121)N-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃, (122)N-Ac-Sar-Gly-Val-D-Leu-Ile-Nva-Ile-Arg-ProNHCH₂CH₃, (123)N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (124)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ile-Ile-Arg-ProNHCH₂CH₃, (125)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nle-Ile-Arg-ProNHCH₂CH₃, (126)N-Ac-Sar-Gly-Val-D-Ile-Thr-Cit-Ile-Arg-ProNHCH₂CH₃, (127)N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O₂)-Ile-Arg-ProNHCH₂CH₃, (128)N-Ac-Sar-Gly-Val-D-Ile-Thr-Arg-Ile-Arg-ProNHCH₂CH₃, (129)N-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃, (130)N-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃, (131)N-Ac-Sar-Gly-Val-D-Ile-Thr-Lys(Ac)-Ile-Arg-ProNHCH₂CH₃, (132)N-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH₂CH₃, (133)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (134)N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (135)N-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (136)N-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (137)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂, (138)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Sar-NHCH₂CH₃, (139)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂, (140)N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (141)N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (142)N-Ac-Sar-Leu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (143)N-Ac-Sar-Phe-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (144)N-Ac-Sar-Glu-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (145)N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (146)N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (147)N-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (148)N-Ac-Asn-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (149)N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (150)N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (151)N-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (152)N-Ac-Glu-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (153)N-Ac-Gaba-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (154)N-Ac-Bala-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (155)N-Ac-Gln-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (156)N-Ac-Sar-Gly-Gly-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (157)N-Ac-Sar-Gly-Glu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (158)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (159)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (160)N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (161)N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (162)N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-Ile-Arg-ProNHCH₂CH₃, (163)N-Ac-Sar-Gly-Val-D-Ile-Thr-Asp-Ile-Arg-ProNHCH₂CH₃, (164)N-Ac-Sar-Gly-Val-D-Ile-Thr-Asn-Ile-Arg-ProNHCH₂CH₃, (165)N-Ac-Sar-Gly-Val-D-Ile-Thr-Met(O)-Ile-Arg-ProNHCH₂CH₃, (166)N-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-Ile-Arg-ProNHCH₂CH₃, (167)N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (168)N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (169)N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (170)N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (171)N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (172)N-Ac-Sar-Gly-Val-D-Cit-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (173)N-Ac-Sar-Gly-Val-D-Hcit-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (174)N-Ac-Sar-Gly-Val-D-Hle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (175)N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (176)N-Ac-Sar-Gly-Val-D-Ile-Thr-Phe(4-CONH₂)-Ile-Arg-ProNHCH₂CH₃, (177)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-His-ProNHCH₂CH₃, (178)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Isp)-ProNHCH₂CH₃, (179)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys(Nic)-ProNHCH₂CH₃, (180)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(Nic)-ProNHCH₂CH₃, (181)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(Isp)-ProNHCH₂CH₃, (182)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-NIsp)-ProNHCH₂CH₃, (183)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cha(4-NIsp)-ProNHCH₂CH₃, (184)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Harg-ProNHCH₂CH₃, (185)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Norarg-ProNHCH₂CH₃, (186)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Cit-ProNHCH₂CH₃, (187)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Lys-ProNHCH₂CH₃, (188)N-Ac-Sar-Gly-Val-D-Ile-Phe(4-CH₂OH)-Nva-Ile-Arg-ProNHCH₂CH₃, (189)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4guanidino)-ProNHCH₂CH₃, (190)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Aminopyrimidinylbutanoyl-Pro-NHCH₂CH₃,(191) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Phe(4-CH₂NHIsp)-ProNHCH₂CH₃,(192)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Gly[4-Pip(N-amidino)]-Pro-NHCH₂CH₃,(193)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala[4-Pip(N-amidino)]-Pro-NHCH₂CH₃,(194) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-guanidino)-ProNHCH₂CH₃,(195)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Ala(3-pyrrolidinylamidino)-Pro-NHCH₂CH₃,(196) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Orn(2-imidazo)-ProNHCH₂CH₃,(197) N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(198) N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (199)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (200)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (201)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (202)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (203)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (204)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂, (205)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂, (206)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (207)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (208)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (209)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (210)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂, (211)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-SarNH₂, (212)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-SarNH₂, (213)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-SarNH₂, (214)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH₂, (215)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH(CH₃)₂, (216)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ser-Ile-Arg-ProNHCH₂CH₃, (217)N-Ac-Sar-Gly-Val-D-Ile-Thr-Orn(Ac)-Ile-Arg-ProNHCH₂CH₃, (218)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂, (219)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂, (220)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-AzaglyNH₂, (221)N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-NHCH₂CH₃,(222) N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,(223)N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-NHCH₂CH₃,(224) N-(2-THFcarbonyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,(225)N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,(226)N-(2-THFcarbonyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-NHCH₂(CH₃)₂,(227) N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(228) N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (229)N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (230)N-(6-Ac-Aca)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (231)N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (232)N-(6-Ac-Aca)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (233)N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (234)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (235)N-(4-Ac-Gaba)-Sar-Gly-Val-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (236)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (237)N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (238)N-(4-Ac-Gaba)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-NHCH(CH₃)₂,(239) N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(240) N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (241)N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (242)N-(2-Furoyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (243)N-(2-Furoyl)-Sar-Gly-Val-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (244)N-(2-Furoyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (245)N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (246)N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (247)N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (248)N-(Shikimyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (249)N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂, (250)N-(Shikimyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (251)N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-NHCH₂CH₃,(252) N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,(253)N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-NHCH₂CH₃,(254) N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,(255)N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-D-AlaNH₂,(256)N-(2-Me-Nicotinyl)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-NHCH(CH₃)₂,(257) N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂, (258)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH(CH₃)₂, (259)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (260)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂, (261)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂, (262)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (263)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (264)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (265)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Leu-Ile-Arg-Pro-D-AlaNH₂, (266)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-Pro-AzaglyNH₂, (267)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHethyl-(1-pyrrolidine),(268)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNH(ethyl-1-cyclohexyl),(269) N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHethyl-(1-pyrrolidine),(270) N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl),(271)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNH(ethyl-1-cyclohexyl),(272) N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, (273)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃, (274)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₂OCH₃, (275)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₂OCH₃, (276)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, (277)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃, (278)N-Succinyl-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₂OCH₃, (279)N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, (280)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₂OCH₃, (281)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-ProNHCH₂CH₃, (282)N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-ProNHCH(CH₃)₂, (283)N-Ac-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂, (284)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂, (285)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Allygly-Ile-Arg-Pro-D-AlaNH₂, (286)N-Ac-Sar-Gly-Val-D-Ile-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃, (287)N-Ac-Sar-Gly-Val-D-Leu-Ser-Allygly-Ile-Arg-Pro-ProNHCH₂CH₃, (288)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SarNH₂, (289)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHOH, (290)N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (291)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃. (292)N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-Ile-Arg-ProNHCH₂CH₃, (293)N-Ac-Sar-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (294)N-Ac-Sar-Gly-Nva-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (295)N-Ac-Sar-Gly-Ile-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (296)N-Ac-Sar-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (297)N-Ac-Sar-Gly-Leu-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (298)N-Ac-Sar-Gly-Ser-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (299)N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (300)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-ProNHCH₂CH₃, (301)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-ProNHCH(CH₃)₂, (302)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂, (303)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂, (304)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Ala-Ile-Arg-Pro-D-AlaNH₂, (305)N-Ac-Sar-Gly-Val-D-Ile-Ser-Ala-Ile-Arg-ProNHCH₂CH₃, (306)N-Ac-Sar-Gly-Val-D-Leu-Ser-Ala-Ile-Arg-ProNHCH₂CH₃, (307)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-ProNHCH₂CH₃, (308)N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-ProNHCH(CH₃)₂, (309)N-Ac-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂, (310)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Val-Ile-Arg-Pro-D-AlaNH₂, (311)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Val-Ile-Arg-Pro-D-AlaNH₂, (312)N-Ac-Sar-Gly-Val-D-Ile-Ser-Val-Ile-Arg-ProNHCH₂CH₃, (313)N-Ac-Sar-Gly-Val-D-Leu-Ser-Val-Ile-Arg-ProNHCH₂CH₃, (314)N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-ProNHCH₂CH₃, (315)N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-ProNHCH(CH₃)₂, (316)N-Ac-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂, (317)N-Ac-Sar-Gly-Val-D-alloIle-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂, (318)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-D-Nva-Ile-Arg-Pro-D-AlaNH₂, (319)N-Ac-Sar-Gly-Val-D-Ile-Ser-D-Nva-Ile-Arg-ProNHCH₂CH₃, (320)N-Ac-Sar-Gly-Val-D-Leu-Ser-D-Nva-Ile-Arg-ProNHCH₂CH₃, (321)N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (322)N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (323)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (324)N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (325)N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (326)N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (327)N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (328)N-Succinyl-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (329)N-Ac-Sar-Gly-Val-D-Ile-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (330)N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (331)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂, CH₂CH₃, (332)N-Ac-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃, (333)N-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (334)N-Ac-Sar-Gly-Val-D-Ile-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (335)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (336)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (337)N-Succinyl-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (338)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₂CH₃, (339)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (340)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (341)N-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (342)N-Ac-Sar-Gly-Val-D-Ile-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (343)N-Ac-Sar-Gly-Val-D-alloIle-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (344)N-Ac-Sar-Gly-Val-D-Leu-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, (345)N-Ac-Sar-Gly-Val-D-Ile-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, (346)N-Ac-Sar-Gly-Val-D-alloIle-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, (347)N-Ac-Sar-Gly-Val-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃, (348)N-Ac-Sar-Gly-Val-D-alloIle-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃, (349)N-Ac-Sar-Gly-Val-D-Leu-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃, (350)N-Ac-Sar-Gly-Val-D-Ile-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃, (351)N-Ac-Sar-Gly-Val-D-alloIle-Tyr-Gln-Ile-Arg-ProNHCH₂CH₃, (352)N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (353)N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (354)N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (355)N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (356)N-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (357)N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (358)N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (359)N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (360)N-Ac-Sar-Gly-Val-D-His-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (361)N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (362)N-Ac-Sar-Gly-Val-D-alloThr-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (363)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH₂CH₃, (364)N-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (365)N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (366)N-Ac-Sar-Gly-Val-D-alloThr-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (367)N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (368)N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (369)N-Ac-Sar-Gly-Val-D-alloThr-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (370)N-Ac-Sar-Gly-Val-D-alloThr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (371)N-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (372)N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-Pro NHCH₂CH₃, (373)N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro NHCH₂CH₃, (374)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-Pro NHCH₂CH₃, (375)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro NHCH₂CH₃, (376)N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-Pro NHCH₂CH₃, (377)N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro NHCH₂CH₃, (378)N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-Pro NHCH₂CH₃, (379)N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro NHCH₂CH₃, (380) (381)(382) N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-Pro CH₂CH₃,(383) N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro NHCH₂CH₃,(384)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,(385) N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHethyl-1-(R)cyclohexyl,(386)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,(387)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,(388)N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-Ile-Arg-ProNHethyl-1-(R)-cyclohexyl,(389)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHethyl-1-(S)-cyclohexyl,(390) N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (391)N-Ac-Sar-Gly-Val-D-Pen-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (392)N-Ac-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (393)N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH(CH₃)₂, (394)N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (395)N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (396)N-Ac-Sar-Gly-Val-D-Pen-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (397)N-Ac-Sar-Gly-Val-D-Pen-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, (398)N-Ac-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (399)N-Ac-Sar-Gly-Val-D-Pen-Thr-Ser-Ile-Arg-ProNHCH₂CH₃, (400)N-Ac-Sar-Gly-Val-D-Pen-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (401)N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (402)N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (403)N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (404)N-Succinyl-Sar-Gly-Val-D-Pen-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (405)N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (406)N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (407)N-Ac-Sar-Gly-Val-D-Cys-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (408)N-Ac-Sar-Gly-Val-D-Cys-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (409)N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH(CH₃)₂, (410)N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (411)N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (412)N-Ac-Sar-Gly-Val-D-Cys-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (413)N-Ac-Sar-Gly-Val-D-Cys-Gly-Gln-Ile-Arg-ProNHCH₂CH₃, (414)N-Ac-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (415)N-Ac-Sar-Gly-Val-D-Cys-Thr-Ser-Ile-Arg-ProNHCH₂CH₃, (416)N-Ac-Sar-Gly-Val-D-Cys-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (417)N-Ac-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (418)N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, (419)N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (420)N-Ac-Sar-Gly-Pen-DIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (421)N-Ac-Sar-Gly-Cys-DIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (422)N-Ac-Sar-Gly-Pen-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (423)N-Ac-Sar-Gly-Pen-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (424)N-Ac-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (425)N-Ac-Sar-Gly-Pen-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (426)N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH(CH₃)₂, (427)N-Ac-Sar-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂, (428)N-Succinyl-Gly-Pen-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (429)N-Succinyl-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (430)N-Succinyl-Sar-Gly-Pen-D-Ile-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (431)N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-Ile-Arg-ProNHCH₂CH₃, (432)N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃, (433)N-Ac-Sar-Gly-Val-D-alloIle-Pen-Nva-Ile-Arg-ProNHCH₂CH₃, (434)N-Ac-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃, (435)N-Ac-Sar-Gly-Val-D-Ile-Pen-Ser-Ile-Arg-ProNHCH₂CH₃, (436)N-Ac-Sar-Gly-Val-D-Ile-Pen-Leu-Ile-Arg-ProNHCH₂CH₃, (437)N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH(CH₃)₂, (438)N-Ac-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-Pro-D-AlaNH₂, (439)N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Nva-Ile-Arg-ProNHCH₂CH₃, (440)N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH₂CH₃, (441)N-Succinyl-Sar-Gly-Val-D-Ile-Pen-Gln-Ile-Arg-ProNHCH(CH₃)₂, (442)N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₂OCH3, (443)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Pen-Ile-Arg-ProNHCH₂CH₃, (444)N-Ac-Sar-Gly-Val-D-Leu-Thr-Pen-Ile-Arg-ProNHCH₂CH₃, (445)N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-Pro-D-AlaNH₂, (446)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH₂CH₃, (447)N-Ac-Sar-Gly-Val-D-Ile-Thr-Pen-Ile-Arg-ProNHCH(CH₃)₂, (448)N-Ac-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃, (449)N-Ac-Sar-Gly-Val-D-Leu-Gly-Pen-Ile-Arg-ProNHCH₂CH₃, (450)N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Pen-Ile-Arg-ProNHCH₂CH₃, (451)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (452)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (453)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (454)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Leu-Ile-Arg-ProNHCH₂CH₃, (455)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Nva-Ile-Arg-Pro-D-AlaNH₂, (456)N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH₂CH₃,(457)N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,(458)N-Succinyl-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Gln-Ile-Arg-ProNHCH(₃)₂,(459) N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,(460) N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Ser-Ser-Ile-Arg-ProNHCH₂CH₃,(461) N-Ac-Sar-Ala-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (462)N-Ac-Sar-Ala-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (463)N-Ac-Sar-Ala-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (464)N-Ac-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (465)N-Ac-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (466)N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (467)N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH₂CH₃, (468)N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-ProNHCH(CH₃)₂, (469)N-Succinyl-Sar-Ala-Val-D-Ile-Thr-Gln-Nva-Ile-Arg-Pro-D-AlaNH₂, (470)N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (471)N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (472)N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (473)N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-DAlaNH₂, (474)N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-Pro-DAlaNH₂, (475)N-(3-Ac-Bala)-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (476)N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (477)N-(3-Ac-Bala)-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (478)N-(3-Ac-Bala)-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (479)N-(3-Ac-Bala)-Sar-Gly-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (480)N-(3-Ac-Bala)-Sar-Ala-Val-D-alloIle-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (481)N-(3-Ac-Bala)-Sar-Ala-Val-D-Ile-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (482)N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (483)N-(3-Ac-Bala)-Sar-Ala-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (484)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH, (485)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-Pro-OH, (486)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ile-Arg-Pro-OH, (487)N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-Pro-OH, (488)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-Pro-OH, (489)N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-OH, (490)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-Pro-OH, (491)N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH, (492)N-Ac-Sar-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-Pro-OH, (493)N-Succinyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH, (494)N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-Pro-OH, (495)N-Ac-Sar-Gly-Asp-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (496)N-Ac-Sar-Gly-Ala-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (497)N-Ac-Sar-Gly-Cha-D-Leu-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (498)N-Ac-Sar-Gly-Met-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (499)N-Ac-Cit-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (500)N-Ac-Sar-Gly-Val-D-Ile-Thr-Hser-Ile-Arg-ProNHCH₂CH₃, (501)N-Ac-Sar-Gly-Val-D-alloIle-His-Nva-Ile-Arg-ProNHCH₂CH₃, (502)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-Butyl, (503)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Butyl, (504)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-iso-Amyl, (505)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-n-hexyl, (506)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3,3-dimethyl)butyl, (507)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-ethoxy)ethyl, (508)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(2-isopropoxy)ethyl, (509)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(3-methoxy)propyl, (510)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-(cyclopentyl)methyl, (511)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH-cyclohexyl, (512)N-Ac-Sar-Gly-Val-allo-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (513)N-Ac-Sar-Gly-Val-D-Lys-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (514)N-Ac-Sar-Gly-Val-D-Trp-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (515)N-Ac-Sar-Gly-Val-D-3,3-Dipheylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (516)N-Ac-Sar-Gly-Val-D-3-Benzothienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (517)N-Ac-Sar-Gly-Val-D-3,4diF-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (518)N-Ac-Sar-Gly-Val-D-Pen(Bzl)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (519)N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-Ile-Arg-ProNHCH(CH₃)₂, (520) (521)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gln-Arg-ProNHCH₂CH₃, (522)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Pro-Arg-ProNHCH₂CH₃, (523)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ser-Arg-ProNHCH₂CH₃, (524)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Trp-Arg-ProNHCH₂CH₃, (525)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂OH, (526)N-Ac-Sar-Ser-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, and (527)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHethyl-1-cyclohexyl.
 13. Acompound according to claim 12, selected from: (1)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (2)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂-(1-pyrrolidine), (3)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH(ethyl-1-(R)-cyclohexyl),(4) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNH₂, (5)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₂CH₃, (6)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (7)N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (8)N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (9)N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (10)N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (11)N-Ac-Sar-Gly-Val-D-3,4-diClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (12)N-Ac-Sar-Gly-Val-D-3-ClPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (13)N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (14)N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (15)N-Ac-Sar-Gly-Val-D-Ile-Thr-Cha-Ile-Arg-ProNHCH₂CH₃, (16)N[2-THF-C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (17)N[6-N-acetyl-(CH₂)₅C(O)]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(18) N-Hexanoyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (19)N-[4-N-Acetylaminobutyryl]-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(20)N—[CH₃C(O)NH—(CH₂)₂—O—(CH₂)₂—O—CH₂—C(O)]-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,(21) N-Ac-Pro-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (22)N-Ac-NEtGly-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (23)N-Ac-Sar-Gly-Val-D-Ile-Thr-Leu-Ile-Arg-ProNHCH₂CH₃, (24)N-Ac-Sar-Gly-Val-D-Ile-Thr-Ser-Ile-Arg-ProNHCH₂CH₃, (25)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH₂, (26)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys(Ac)-Arg-ProNHCH₂CH₃, (27)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH₂CH₃, (28)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH₂CH₃, (29)N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allylgly-Arg-ProNHCH₂CH₃, (30)N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-Ile-Arg-ProNHCH₂CH₃, (31)N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-Ile-Arg-ProNHCH₂CH₃, (32)N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-Ile-Arg-ProNHCH₂CH₃, (33)N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-Ile-Arg-ProNHCH₂CH₃, (34)N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-Ile-Arg-ProNHCH₂CH₃, (35)N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-Ile-Arg-ProNHCH₂CH₃, (36)N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-Ile-Arg-ProNHCH₂CH₃, (37)N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (38)N-Ac-Sar-Gly-Val-D-Leu-Allylgly-Nva-Ile-Arg-ProNHCH₂CH₃, (39)N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (40)N-Ac-Sar-Gly-Val-D-Ile-Thr-Tyr-Ile-Arg-ProNHCH₂CH₃, (41)N-Ac-Sar-Gly-Val-D-Ile-Thr-Glu-Ile-Arg-ProNHCH₂CH₃, (42)N-Ac-Sar-Gly-Val-D-Ile-Thr-Propargylgly-Ile-Arg-ProNHCH₂CH₃, (43)N-Ac-Sar-Gly-Val-D-alloIle-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, (44)N-Ac-Bala-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (45)N-Phenylacetyl-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (46)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-AzaglyNH₂, (47)N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-SerNH₂, (48)N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (49)N-(6-Ac-Aca)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (50)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (51)N-(4-Ac-Gaba)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (52)N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (53)N-(2-Furoyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (54)N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃, (55)N-(Shikimyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃, (56) (57)(58) N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH₂CH₃,(59) N-(2-Me-nicotinyl)-Sar-Gly-Val-D-Leu-Ser-Nva-Ile-Arg-ProNHCH₂CH₃,(60) N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-OH, (61)N-Ac-Sar-Ala-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (62)N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, (63)N-Ac-Sar-Gly-Val-D-Phe(3,4,5-triF)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, and (64)N-Ac-Sar-Gly-Val-D-Phe(4-NH₂)-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 14. Acompound, or a pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, selected from the group consisting ofN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, andN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃.
 15. Thecompound, or pharmaceutically acceptable salt, ester, solvate, orprodrug thereof which isN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 16. The compound, orpharmaceutically acceptable salt, ester, solvate, or prodrug thereof,which is N-Ac-Sar-Gly-Val-D-alloIle-Thr-Ile-Arg-ProNHCH₂CH₃.
 17. Thecompound, or pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, which isN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃.
 18. The compound, orpharmaceutically acceptable salt, ester, solvate, or prodrug thereof,which is N-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃.
 19. Acomposition comprising a compound, or a pharmaceutically acceptablesalt, ester, solvate, or prodrug thereof, selected from the groupconsisting of N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, andN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, and apharmaceutically acceptable carrier.
 20. A composition comprisingN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 21. A composition comprisingN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 22. A composition comprisingN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 23. A composition comprisingN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 24. A composition comprisinga compound, or a pharmaceutically acceptable salt, ester, solvate, orprodrug thereof selected from the group consisting ofN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, andN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, and apharmaceutically acceptable carrier.
 25. A composition comprisingN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 26. A composition comprisingN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 27. A composition comprisingN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 28. A composition comprisingN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,and a pharmaceutically acceptable carrier.
 29. A composition comprisinga pharmaceutically acceptable carrier in combination with a compoundaccording to claim 1 in an amount effective to inhibit angiogenesis. 30.A composition comprising a pharmaceutically acceptable carrier incombination with a compound according to claim 12 in an amount effectiveto inhibit angiogenesis.
 31. A composition comprising a pharmaceuticallyacceptable carrier in combination with a compound selected from thegroup consisting of N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, andN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, in an amounteffective to inhibit angiogenesis.
 32. A composition according to claim31 wherein the compound isN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 33. A compositionaccording to claim 31 wherein the compound isN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 34. Acomposition according to claim 31 wherein the compound isN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃.
 35. A compositionaccording to claim 31 wherein the compound isN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃.
 36. Acomposition comprising a pharmaceutically acceptable carrier incombination with a compound according to claim 1 in an amount effectiveto inhibit proliferation of tumor cells.
 37. A composition comprising apharmaceutically acceptable carrier in combination with a compoundaccording to claim 12 in an amount effective to inhibit proliferation oftumor cells.
 38. A composition comprising a pharmaceutically acceptablecarrier in combination with a compound selected from the groupconsisting of N-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃,N-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃, andN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃, in an amounteffective to inhibit proliferation of tumor cells.
 39. A compositionaccording to claim 38 wherein the compound isN-Ac-Sar-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 40. A compositionaccording to claim 38 wherein the compound isN-Ac-Sar-Gly-Val-D-alloIle-Thr-Nva-Ile-Arg-ProNHCH₂CH₃.
 41. Acomposition according to claim 38 wherein the compound isN-Ac-Sar-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH₂CH₃.
 42. A compositionaccording to claim 38 wherein the compound isN-Ac-Sar-Gly-Val-D-alloIle-Ser-Ser-Ile-Arg-ProNHCH₂CH₃.